Lung Cancer (2004) 45, 221—225

Single agent gefitinib as first line therapy inpatients with advanced non-small cell lungcancer: Washington University Experience

Aruna Kommareddya, Margaret A. Coplina, Feng Gaob,Danelle Behnkena, Edie Romvari a, William Readc,Ramaswamy Govindana,*

a Division of Medical Oncology, Alvin J. Siteman Cancer Center, Washington University School ofMedicine, 4960 Children’s Place, P. O. Box 8056, St. Louis, MO 63110, USAb Division of Biostatistics, Alvin J. Siteman Cancer Center, Washington University School of Medicine,660 South Euclid, P. O. Box 8067, St. Louis, MO 63110, USAc Department of Medicine, University of California, San Diego, USA

Received 16 October 2003 ; received in revised form 13 January 2004; accepted 15 January 2004

KEYWORDSGefitinib;Non-small cell lungcancer;First line treatment

Summary Gefitinib has modest activity with an overall response rate of 11—18% inpatients with metastatic non-small cell lung cancer (NSCLC) who have had progres-sive disease following platinum containing chemotherapy. However, the efficacy ofgefitinib in previously untreated metastatic NSCLC is not known. We retrospectivelyanalyzed the efficacy of gefitinib as a first line therapy in 26 patients with advancedNSCLC enrolled in the expanded access program. Patients received gefitinib 250mga day orally if they had a poor performance status (PS) or if they refused cytotoxicchemotherapy. Treatment was continued as long as there was no evidence of diseaseprogression or unacceptable treatment related toxicities. The characteristics of 25evaluable patients enrolled between the period of May 2001 and August 2002 include:15 women, 10men;median age 73 years (range 56—86), 81% had an ECOG performancestatus of two. Only one patient had a partial response and 32% had stable disease astheir best response for a disease control rate of 36%; 32% of patients had diseasecontrol lasting 5 months or longer. The median overall survival and progression-freesurvival (PFS) were 14.1 and 2.9 months, respectively. Toxicities were minimal andincluded rash and diarrhea. Gefitinib was well tolerated and had interesting activityin previously untreated patients with advanced NSCLC.© 2004 Elsevier Ireland Ltd. All rights reserved.

1. Introduction

The 1 year survival rate for metastatic NSCLC isapproximately 38% with a 2 year survival of 10%

*Corresponding author. Tel.: +1-314-362-4819;fax: +1-314-362-7086.

E-mail address: rgovinda@im.wustl.edu (R. Govindan).

[1]. Even though, systemic chemotherapy improvesthe quality of life and survival of patients with ad-vanced non-small cell lung cancer (NSCLC) whencompared with best supportive care a plateau hasbeen reached in terms of survival with combina-tion chemotherapy [2]. Novel approaches are be-ing pursued including the use of targeted therapiesin advanced NSCLC. The epidermal growth factor

0169-5002/$ – see front matter © 2004 Elsevier Ireland Ltd. All rights reserved.doi:10.1016/j.lungcan.2004.01.022

222 A. Kommareddy et al.

receptor (EGFR) represents one potential target asactivation of EGFR signal transduction pathway re-sults in cell proliferation, increased angiogenesis,and inhibition of apoptosis [3]. EGFR inhibition de-creases angiogenesis, cell proliferation, and pro-motes apoptosis [4,5].Gefitinib (ZD1839, Iressa®, AstraZeneca Pharma-

ceuticals, LP, Wilmington, DE) is an orally active,selective epidermal growth factor receptor tyro-sine kinase inhibitor (EGFR-TKI) that blocks signaltransduction pathways implicated in proliferationand survival of cancer cells [6]. In vitro, gefitinibis active against cells with a wide range of epider-mal growth factor receptor levels, although it ismore active in cells with higher epidermal growthfactor receptor expression [7]. Phase I clinical stud-ies demonstrated that gefitinib is well toleratedand active in patients with NSCLC [8]. Two largemulticenter, randomized phase II studies (IDEAL 1and 2) undertaken in Japan and the United Statesreported response rates of 18.4 and 11.8%, respec-tively [9,10]. The median progression-free survival(PFS) was 2.7 and 1.9 months, and the medianoverall survival was 7.6 and 6.5 months in IDEAL 1and 2, respectively. Both studies included patientswho had progressive disease following cytotoxicchemotherapy. To our knowledge, there have beenno reports with the use of gefitinib as a first linetherapeutic agent in NSCLC.

2. Patients and methods

We retrospectively analyzed safety and efficacydata from patients with previously untreatedmetastatic NSCLC who received gefitinib monother-apy. This patient population was selected from alarger database of patients with advanced NSCLCwho were enrolled under the expanded accessprogram as described below. The nonrandomized,open-label, expanded access clinical program wasinitiated in May 2001 at the Washington UniversitySchool of Medicine. A total of 171 patients had beenenrolled as of 30 August 2002. Under this program,sponsored by Astra Zeneca Pharmaceuticals andadministered by the National Organization of RareDiseases, patients with advanced NSCLC receivedgefitinib of 250mg orally once daily. A complete his-tory and physical examination was required beforeenrollment. Patients underwent baseline radiologicevaluation within 28 days before initiating therapyand a follow up was performed at 2—3 monthlyintervals. Most of the patients were followed withserial computerized tomography (CT) scans andone patient was followed by chest X-ray (CXR).Treatment was continued so long as the treating

physician determined that there was clinical ben-efit without unacceptable toxicity. Toxicity wasassessed using the National Cancer Institute (NCI)toxicity criteria and response was assessed usingthe Response Evaluation Criteria in Solid Tumors(RECIST). Initial response evaluation was based onradiologic and clinical evaluation performed after2—3 months of treatment initiation. Patients whohad stable disease or patients with progressive dis-ease who were alive as of that date were followedfor outcomes subsequently. Dates of last clinicalcontact in patients with stable disease and datesof death or dates of last contact in patients withprogressive disease were documented.

3. Statistical analysis

For the overall survival analysis, the date of deathor date of the last clinical contact was used as theend point. Progression-free survival was defined asthe period from the date of study entry to the datewhen disease progression (or death) was observed.Kaplan—Meier product limit estimators were used

to describe the distributions of overall survival andprogression-free survival. Log-rank test was used tocompare the survival outcomes between men andwomen.

4. Results

Between 11/26/01 and 8/30/02, 26 patients withadvanced NSCLC who did not receive any priorchemotherapy were treated with gefitinib. Theclinical characteristics are shown in Table 1. Of the26 patients, 11 were men and 15 were women. Pa-tients had a median age of 73 years (range 56—86years) and had an ECOG performance status (PS)ranging from 1 to 3, with the majority of patientsbeing PS 2 (n = 21). Twenty-four patients had stageIV disease and two patients had stage III disease atenrollment. Thirty percent of patients had adeno-carcinoma of the broncho-alveolar type (BAC) and30% of patients had adenocarcinoma without BACfeatures.

4.1. Response

Seven patients (28%) died before radiologic evalua-tion for response could be performed (range: 1—9.6weeks), one patient discontinued treatment after5 days secondary to fatigue and generalized weak-ness. One patient was lost to follow up immedi-ately after receiving therapy before any radiologicassessment was completed and was excluded from

Single agent gefitinib in patients with advanced non-small cell lung cancer 223

Table 1 Patient characteristics

Variable Number Percentage

Patient number 26 —Men/women 11/15 42/58

Age (years)Mean (range) 73 (56—86) —Median 73

ECOG performance status1 1 3.82 21 80.73 4 15.4

HistologyAdenocarcinoma 8 30.8Bronchoalveolar carcinoma 8 30.8Squamous cell carcinoma 6 23Other NSCLC 4 15.4

Disease stageIII 2 7.7IV 24 92.3

analysis. Of the 25 evaluable patients, one patientexperienced a partial remission; eight patients(32%) had stable disease as their best response fora total disease control rate (PR+ SD) of 36%. Ofthese patients seven were women, two were men,4 had adenocarcinoma of the BAC type, two hadadenocarcinoma, two had squamous histology and

Follow-up time (days)

Pro

babi

lity

of s

urvi

val

0 100 200 300 400 500

0.0

0.2

0.4

0.6

0.8

1.0

Overall survivalProgression-free survival

Fig. 1 Kaplan—Meier survival curves of the 25 evaluable patients: the solid line represents the overall survival andthe dotted line represents the progression-free survival.

one had NSCLC unspecified. Eight patients had CTscans documenting progressive disease at the timeof their initial assessment, after median treatmentduration of 11.7 weeks (range 8—16 weeks).Subsequent follow up of the eight patients with

stable disease showed that two patients had pro-gressive disease after total treatment duration of21.4 and 47 weeks, respectively. One patient waslost to follow up after 21.8 weeks of treatment andfive patients remain with stable disease as of theirlast CT scan, with a median duration of treatmentof 47.6 weeks (range: 30.4—64.4 plus weeks). Twoof the patients with progression went on to receivechemotherapy, one patient received single agentvinorelbine and the other patient received com-bination therapy with irinotecan and carboplatin.Majority (75%) of the patients with stable diseasehad an initial PS of 2, one patient had a PS of 1,and another patient had a PS of 3. Of the eightpatients with documented progressive disease, fivewere still alive as of the end of March 2003. Of thesepatients one patient received single agent gemc-itabine initially and was subsequently switched todual agent therapy with gemcitabine and carbo-platin, another patient received gemcitabine andsubsequently vinorelbine upon disease progression,another patient received gemcitabine and carbo-platin and the fourth patient was offered combina-tion chemotherapy but was lost for follow up. Threepatients died within 2 months of documented pro-gression.

224 A. Kommareddy et al.

4.2. Overall and progression-free survival

The median overall survival and progression-freesurvival were 14.1 and 2.9 months, respectively.The 1 year overall survival rate in this populationwas 55% (95% confidence intervals: 37—82%) and the1 year progression-free survival was 20% (95% confi-dence intervals: 6—56%), respectively. (Fig. 1) Thesurvival outcomes for women and men were com-pared by log-rank tests. Results show that men hada poorer prognosis in terms of overall survival andprogression-free survival (P-values 0.008 and 0.013,respectively) compared with women. Due to smallsample size, no subgroup analysis was performedassessing the outcomes related to the histology andperformance status.

4.3. Safety and tolerability

Toxicities were minimal and included 6 patientswith skin rash (three patients with grade one,three patients with grade two toxicities) and sixpatients with diarrhea (three patients with gradeone, three patients with grade two toxicities). Onepatient had grade three mucositis and dysphagiarequiring gefitinib to be stopped after 1 month oftreatment. Another patient had grade two mucosi-tis requiring medication to be held temporarily.One patient had a cerebrovascular accident andanother patient had ileus during treatment thatwere not related to metastatic cancer and proba-bly not related to treatment, but treatment wastemporarily suspended and reinstituted once theacute process resolved. One patient had brittlenails, and another patient had fatigue and general-ized weakness and discontinued medication after 5days. No autopsies were performed on patients whodied without radiologically documented progres-sion.

5. Discussion

It has been shown that chemotherapy improvesthe quality of life and survival in patients withadvanced NSCLC compared with best supportivecare alone [11,12]. However, most of the prospec-tive clinical studies with combination or singleagent chemotherapy do not include patients withco-morbid conditions or poor performance status[13—15]. Because a significant number of patientswith advanced NSCLC have poor performance sta-tus and co-morbid conditions at diagnosis, it iscritical to evaluate novel therapeutic agents withfavorable toxicity profile.

Our retrospective analysis demonstrates thatoral gefitinib is well tolerated and has anti-tumoractivity in this population of chemotherapy naıvepatients. Side effects were minimal and consistedmostly of grade two or less diarrhea and rash. Mostof the patients who had disease progression af-ter a period of stabilization, initially ineligible forchemotherapy went on to receive combination orsingle agent chemotherapy as a result of improve-ment in performance status. Our response rates arelower than that obtained in the two prospectivestudies that evaluated gefitinib in advanced NSCLC[9,10]. However, it should be noted that a signif-icant proportion of our patients had a poor per-formance status and 28% of patients died within 2months of treatment initiation. Because of the ret-rospective nature of the analysis, no formal assess-ments were made regarding the quality of life ofthe patients. In conclusion, our retrospective anal-ysis demonstrates that gefitinib is well toleratedand has modest activity in previously untreatedmetastatic NSCLC. Prospective studies need to beconducted to evaluate the role of gefitinib in pa-tients with previously untreated metastatic NSCLC.

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