Originally published as JCO Early Release 10.1200/JCO.2003.10.038 on May 14 2003
Journal of Clinical Oncology, Vol 21, Issue 12
(June), 2003: 2237-2246
© 2003 American Society for Clinical Oncology
Multi-Institutional Randomized Phase II Trial of Gefitinib for Previously Treated Patients With Advanced Non–Small-Cell Lung Cancer
Masahiro Fukuoka,
Seiji Yano,
Giuseppe Giaccone,
Tomohide Tamura,
Kazuhiko Nakagawa,
Jean-Yves Douillard,
Yutaka Nishiwaki,
Johan Vansteenkiste,
Shinzoh Kudoh,
Danny Rischin,
Richard Eek,
Takeshi Horai,
Kazumasa Noda,
Ichiro Takata,
Egbert Smit,
Steven Averbuch,
Angela Macleod,
Andrea Feyereislova,
Rui-Ping Dong,
José Baselga
From the Kinki University School of Medicine, Osaka City University School of Medicine, and AstraZeneca, Osaka, Tokushima University School of Medicine, Tokushima, National Cancer Center, Central Hospital, and Japanese Foundation for Cancer Research, Tokyo, National Cancer Center, East Hospital, Chiba, Kanagawa Cancer Center, Yokohama, and National Shikoku Cancer Center, Matsuyama, Japan; C.R.L.C.C. Rene Gauducheau, Saint-Herblain, France; University Hospital Gasthuisberg, Leuven, Belgium; Centre for Developmental Cancer Therapeutics, Melbourne, Australia; Mary Potter Oncology Centre, Pretoria, South Africa; Academic Hospital Free University, Amsterdam, the Netherlands; AstraZeneca, Wilmington, DE; AstraZeneca, Alderley Park, United Kingdom; and Vall d’Hebron University Hospital, Barcelona, Spain.
Address reprint requests to Masahiro Fukuoka, MD, Fourth Department of Internal Medicine, Kinki University School of Medicine, 377-2 Ohnohigashi Osakasayama, Osaka 589, Japan; email: mfukuoka{at}med.kindai.ac.jp.
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ABSTRACT
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Purpose: To evaluate the efficacy and tolerability of two doses of gefitinib (Iressa [ZD1839]; AstraZeneca, Wilmington, DE), a novel epidermal growth factor receptor tyrosine kinase inhibitor, in patients with pretreated advanced non–small-cell lung cancer (NSCLC).
Patients and Methods: This was a randomized, double-blind, parallel-group, multicenter phase II trial. Two hundred ten patients with advanced NSCLC who were previously treated with one or two chemotherapy regimens (at least one containing platinum) were randomized to receive either 250-mg or 500-mg oral doses of gefitinib once daily.
Results: Efficacy was similar for the 250- and 500-mg/d groups. Objective tumor response rates were 18.4% (95% confidence interval [CI], 11.5 to 27.3) and 19.0% (95% CI, 12.1 to 27.9); among evaluable patients, symptom improvement rates were 40.3% (95% CI, 28.5 to 53.0) and 37.0% (95% CI, 26.0 to 49.1); median progression-free survival times were 2.7 and 2.8 months; and median overall survival times were 7.6 and 8.0 months, respectively. Symptom improvements were recorded for 69.2% (250 mg/d) and 85.7% (500 mg/d) of patients with a tumor response. Adverse events (AEs) at both dose levels were generally mild (grade 1 or 2) and consisted mainly of skin reactions and diarrhea. Drug-related toxicities were more frequent in the higher-dose group. Withdrawal due to drug-related AEs was 1.9% and 9.4% for patients receiving gefitinib 250 and 500 mg/d, respectively.
Conclusion: Gefitinib showed clinically meaningful antitumor activity and provided symptom relief as second- and third-line treatment in these patients. At 250 mg/d, gefitinib had a favorable AE profile. Gefitinib 250 mg/d is an important, novel treatment option for patients with pretreated advanced NSCLC.
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INTRODUCTION
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LUNG CANCER is the most common cause of cancer deaths in both men and women worldwide.1 Despite advances in treatment, such as combination chemotherapy and chemoradiation, survival has improved very little over the past few decades.2 A meta-analysis demonstrated that the median survival time for patients with advanced disease receiving cisplatin-based chemotherapy is around 6 months.3 The 5-year survival rate for all stages is less than 15%.4 Prognosis is particularly poor for patients who have progressive disease following chemotherapy; for non–small-cell lung cancer (NSCLC) patients receiving best supportive care (BSC) after 1 or more prior chemotherapy regimen, median survival time is just 16 weeks, with a 1-year survival rate of 16%.5
Recently, it has become generally accepted that systemic chemotherapy is beneficial in terms of improved survival and quality of life (QoL) in those with advanced NSCLC.3,6 As more patients receive first-line chemotherapy, the need for effective second-line therapy is increasing. Currently, docetaxel, having demonstrated survival benefits over BSC, is the only approved treatment in the United States and the European Union for patients who have been failed by previous platinum-based chemotherapy.7
Patients with late-stage NSCLC are often symptomatic, with specific pulmonary problems (eg, cough, breathlessness, hemotypsis) and general symptoms (eg, fatigue, weight loss) that can cause extreme distress to the patient. Therefore, improvements in disease-related symptoms and QoL are the key desired outcomes of medical management.8 Effective, palliative, low-toxicity treatments for patients with advanced NSCLC are needed.
The epidermal growth factor receptor (EGFR) is a promising target for anticancer therapy because it is expressed or highly expressed in a variety of tumors, including NSCLC.9,10 Furthermore, high levels of EGFR expression have been associated with a poor prognosis in lung cancer patients in several studies.11–13 EGFR-targeted cancer therapies are currently being developed; strategies include inhibition of the intracellular tyrosine kinase domain of the receptor by small molecules such as gefitinib (Iressa [ZD1839]; AstraZeneca, Wilmington, DE).14 Gefitinib is an orally active, selective EGFR tyrosine kinase inhibitor that blocks signal transduction pathways implicated in the proliferation and survival of cancer cells.15,16
Four phase I studies assessed gefitinib tolerability and pharmacokinetics in pretreated patients with solid tumors, including 100 patients with heavily pretreated advanced NSCLC.17 Evidence of major tumor regression was seen in 10 patients with NSCLC; a number of other patients had nonprogressive disease lasting for 6 months or longer; and palliation of specific symptoms was also frequently observed. In these trials, responses were seen across the dose range 150 to 800 mg/day, while the majority of dose interruptions and reductions due to toxicity were required in patients receiving more than 600 mg/d. From these data, two doses (250 and 500 mg/d) were selected for investigation in phase II and phase III trials. The 250 mg/d dose is higher than the lowest dose level at which objective tumor regression was seen, while 500 mg/d is the highest dose that was well tolerated when taken over an extended period in phase I trials.
The aims of this Iressa Dose Evaluation in Advanced Lung Cancer (IDEAL 1) trial were to further investigate the efficacy and safety of oral gefitinib in patients with advanced NSCLC who had previously received one or two chemotherapy regimens, with at least one containing platinum. The population was prospectively stratified into Japanese and non-Japanese patients to investigate whether there were any differences between the two patient populations with respect to efficacy.
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PATIENTS AND METHODS
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Study Design
This randomized, double-blind, parallel group, phase II multicenter trial recruited patients at 43 centers across Europe, Australia, South Africa, and Japan. Primary objectives were to evaluate the objective tumor response rate (RR) for gefitinib doses of 250 and 500 mg/d and to further characterize the safety profile of these doses. Secondary objectives were to estimate disease-related symptom improvement rate, disease control rate (response + stable disease), progression-free survival (PFS), and overall survival (OS); to evaluate changes in QoL; and to assess any differences between Japanese and non-Japanese patients with respect to efficacy and safety.
Patient Eligibility
Eligibility criteria were histologic or cytologic confirmation of locally advanced or metastatic NSCLC; stage III or stage IV disease not curable with surgery or radiotherapy at study entry; recurrent or refractory disease following one or two previous chemotherapy regimens (at least one containing platinum); at least one bidimensionally measurable or radiographically assessable lesion; age of 18 years or older; World Health Organization performance status (PS) of 0 to 2; and life expectancy of 12 weeks or longer. Patients with stable brain metastases were eligible. Exclusion criteria were more than two previous chemotherapy regimens, systemic anticancer therapy within 21 days, or radiotherapy within 14 days before the start of treatment; unresolved chronic toxicity higher than the National Cancer Institute common toxicity criteria (NCI-CTC, version 2) grade (G) of 2 (excluding cases of alopecia); ALT or AST levels greater than 2.5 times the upper limit of reference range (ULRR; more than 5 times the ULRR in the presence of liver metastases); serum creatinine levels greater than 1.5 times the ULRR; serum bilirubin levels greater than 1.25 times the ULRR; and neutrophils less than 1.5x109/L or platelets less than 75x109/L. Patients gave informed consent, and trial document approval was obtained from the ethics committee or institutional review board at each trial center. The study was performed in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines.
Treatment
Patients were randomly assigned to receive double-blind gefitinib doses at 250 or 500 mg/d. Tablets were administered once daily, except on day 1 when patients received two doses approximately 12 hours apart. Patients continued uninterrupted treatment until disease progression, intolerable toxicity, withdrawal of consent, or trial closure (4 months after the last patient was recruited). Patients without progression were permitted to continue gefitinib treatment in a further study.
One dose reduction per patient was permitted in the event of unacceptable toxicity. New blinded treatment supplies, decreasing the dose from 500 mg to 250 mg or from 250 mg to 100 mg, were dispensed. Gefitinib administration could be interrupted for a maximum of 14 days.
No systemic anticancer treatment was permitted during the trial, except for palliative radiotherapy in patients with isolated symptomatic bone metastases, and as long as trial drug administration was not interrupted for longer than 14 days.
Efficacy
We assessed objective tumor response as complete response (CR), partial response (PR), partial response in nonmeasurable disease (PRNM), stable disease (SD), or progressive disease (PD) in accordance with the Southwest Oncology Group modification of Union Internationale Contre le Cancer/WHO criteria.18 Baseline assessments were performed within 14 days before randomization. After the start of treatment, assessments were performed every 4 weeks, then every 8 weeks following the fourth month. An independent response evaluation committee consisting of three radiologists/oncologists at each session reviewed images of patients with CR, PR, and SD; reviewers were blinded to the investigators’ assessment and dose of gefitinib. Duration of response was defined as the time from the first objective assessment of CR or PR to the first instance of progression or death.
Disease Control
Disease control was defined as the best tumor response of CR, PR, or SD that was confirmed and sustained for 4 weeks or longer.
Disease-related symptom improvement was measured using the Lung Cancer Subscale (LCS), a validated subscale of the QoL instrument, the Functional Assessment of Cancer Therapy – Lung (FACT-L) questionnaire (Fig 1 ).19 Patients completed a weekly diary card rating the severity of each of the following seven LCS items on a scale of 0 to 4: shortness of breath, weight loss, lack of clear thinking, coughing, loss of appetite, tightness in the chest, and difficulty breathing. On day 28, the LCS was completed as part of the entire FACT-L questionnaire. The maximum (asymptomatic) attainable score was 28. Patients with a baseline LCS score of 24 or lower were evaluable for symptom improvement. This information was used to determine symptom improvement rate, time to symptom improvement, and duration of symptom improvement. Based on data showing that a 2-point change in LCS score is clinically meaningful for patients and is significantly associated with Eastern Cooperative Oncology Group performance status, weight loss, objective tumor response, and time to progression,20 symptom improvement was prospectively defined as a 2-point (or greater) improvement in LCS score sustained for 4 weeks or longer, with no worsening at any interim weekly time points. Duration of symptom improvement was defined as the interval between the first visit presenting with symptom improvement and a subsequent visit at which symptoms had worsened. Missing data points were counted as no change in symptoms.
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Fig 1. The five components of the Functional Assessment of Cancer Therapy - Lung (FACT-L). Component 1 is measured by the Lung Cancer Subscale itself; components 1 through 3, by the Trial Outcome Index; and components 1 through 5, by FACT-L.
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QoL Assessment
Patients completed the FACT-L questionnaire to assess QoL. The FACT-L assessment has been validated with respect to its psychometric properties and sensitivity to clinical changes.19 FACT-L was completed at baseline and then every 28 days after the start of treatment. The questionnaire was administered before clinical assessment and before patients heard news about their disease status. The Trial Outcome Index (TOI) of FACT-L (Fig 1 ) measures the more physical aspects of patient QoL that are shown to be sensitive to chemotherapy.19 TOI and FACT-L scores were derived in a similar manner to the LCS scores; the highest scores attainable for TOI and FACT-L were 84 and 136, respectively. TOI and FACT-L responses were prospectively defined as a 6-point (or greater) improvement (for 4 weeks or longer), a change that has been shown to be clinically meaningful.20
PFS and OS
PFS was defined as the period from the randomization date to the date when disease progression (or death) was observed. OS was defined as the period from the randomization date to the date of death. Patients alive at data cutoff were censored at the last date the patient was known to be alive.
Safety and Tolerability
All adverse events (AEs) were reported, and severity was assessed by the NCI-CTC (version 2.0) grading system. Data were collected on therapy interruptions and withdrawals due to AEs. Routine clinical and laboratory assessments were performed. ECGs and complete ophthalmic evaluations, including slitlamp examination, were performed at baseline, at 4 months, and on completion of or withdrawal from the trial.
Statistical Methods
Patients were randomized to receive oral gefitinib at doses of 250 or 500 mg/d, and were stratified by ethnicity as Japanese and non-Japanese. Randomization and allocation were performed by a centralized registration or randomization center using dynamic balancing21 with factors for country and WHO-PS of 0 to 1 versus 2. Patients were categorized at randomization with respect to prior taxane therapy (docetaxel ± paclitaxel v paclitaxel alone v no taxane) and number of prior regimens (one v two).
The target sample population of 200 patients (100 in each dose group and 100 in each ethnic group) was chosen to enable the tumor lower limit for RR to be independently evaluated in the four strata defined by dose and ethnicity. Within each stratum, the goal was to have 90% power for a two-sided 5% significance test to show that the RR was greater than 5% assuming that the actual RR was 20%, which required 45 or more evaluable patients per stratum.
RRs and disease control rates were compared between strata using Fisher’s exact test. Logistic regression models were used to further explore observed differences and to identify baseline factors that may independently predict for tumor response and disease control. PFS and OS were compared between strata using the log-rank test. Further analyses were conducted on these data using Cox’s proportional hazard modeling.
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RESULTS
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Patients
A total of 210 patients were randomized within 4 months (October 2, 2000 to January 30, 2001). Of these, 208 patients were evaluable for efficacy, and 209 patients were evaluable for safety (Fig 2). The two dose groups were well balanced for most baseline demographic factors, with the exception of sex (Table 1). As planned, approximately half of the patients randomized were Japanese. There were some demographic imbalances between the Japanese and non-Japanese populations (62.7% v 77.8% male; 20.6% v 15.7% PS of 0; 8.8% v 16.7% PS of 2; and 76.5% v 50.0% adenocarcinoma, respectively).
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Fig 2. Number of patients included in the analysis populations. (A) Patients who received 1 or more doses of trial treatment. (B) Patients who received 14 or more days of trials treatment in each 28-day treatment period before the first tumor assessment recorded their best tumor response. (C) Patients with a Lung Cancer Subscale score of 24 or lower. Asterisk indicates that this patient’s last dose of systemic anticancer therapy was received within 21 days prior to the start of trial treatment.
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Efficacy
The investigator assessments of the best overall tumor responses are shown in Table 2. RR was 18.4% for the 250-mg/d group, which was not statistically different from that of the 500-mg/d group (RR, 19.0%; Table 2). The independent response evaluation committee reviewed 107 of the 110 patients whom the investigator considered to have CR, PR, PRNM or SD. These included 38 of the 39 responders. There was a high concordance in tumor response evaluation between investigators and independent reviewers (73.8%; Table 3). In addition, the response evaluation committee evaluated an additional 25 patients who were assessed by the investigators as having a best response of PD. Of these 25 patients, the response evaluation committee considered 7 patients to have had a best response of SD.
Of the patients who responded, most showed rapid tumor regression, with 68% meeting the criteria for objective response by the first postbaseline assessment. The remaining patients met the criteria in the second, third, or fourth month following randomization. Furthermore, across both doses, most responders (87.2%) still had a response at the data cutoff, with a median follow-up of 6.3 months (range, 4.0–7.9 months). For patients who responded, median duration of response was more than 3 months (ranges: 250-mg/d group, 1–5 months; 500-mg/d group, 1–5.5 months). RRs were similar irrespective of whether gefitinib was used as second-line (17.5%, 250 mg/d; 18.3%, 500 mg/d) or third-line treatment (19.6%, 250 mg/d; 20.0%, 500 mg/d). A post hoc nonrandomized analysis showed that RRs for the subgroup of patients who had previously received a platinum and a taxane were 24.0% at 250 mg/d and 28.0% at 500 mg/d. Similarly, RRs for patients previously given platinum and docetaxel were 24.0% at 250 mg/d and 26.0% at 500 mg/d. RRs for patients who had progressed on two prior chemotherapy regimens were 13.6% at 250 mg/d and 7.9% at 500 mg/d.
As expected, the mean number of days under treatment was higher for responders than for nonresponders (150 v 68 days, respectively); however, the number of days under treatment, as compared with the number of days under the trial was 95% versus 96% in both groups.
Disease Control
The disease control rate was 54.4% for the 250-mg/d group, which was not statistically different from that of the 500-mg/d group, 51.4% (P = .68; Table 2). Median duration of disease control for patients who responded or had stable disease was 3.2 and 4.6 months, respectively. Disease control was similar for second-line (59.6%, 250 mg/d; 50.0%, 500 mg/d) and third-line treatment (47.8%, 250 mg/d; 53.3%, 500 mg/d). SD rate was 35.9% at 250 mg/d and 32.4% at 500 mg/d.
Disease-Related Symptom Improvement
Evaluable baseline questionnaires were received from 80 and 81 patients from the 250- and 500-mg/d groups, respectively. Of these, 67 and 73 patients, respectively, were evaluable for symptom improvement. Median baseline scores for LCS were 18.0 (ranges: 250 mg/d, 4–24; 500 mg/d, 2–24) for each dose group, indicating that this was a symptomatic population. The symptom improvement rate was 40.3% (95% confidence interval [CI], 28.5 to 53.0) for the 250-mg/d group and 37.0% (95% CI, 26.0 to 49.1) for the 500-mg/d group. Most patients with a tumor response who were evaluable for symptom improvement also showed an improvement in their disease-related symptoms, and more than 50% of the patients with SD also had symptom improvement (Fig 3).
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Fig 3. Symptom improvement benefits by tumor response. CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease.
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The median of the maximum change in LCS score for the patients with symptom improvement was 7.0 points (range, 3–17 points) during the first interval of improvement (time between the first visit response of improved, to the subsequent response of worsened). Importantly, median time to symptom improvement was only 8 days (the time of first postbaseline assessment) for both doses. Median duration of symptom improvement was 5.1 month (range, 1.1–5.6+ months) at 500 mg/d. At 250 mg/d, the median duration of symptom improvement was not calculable because patients were still responding at the time of data cutoff; symptom improvement lasted for at least 3 months in 75% of patients and for 6 months in 65% of patients. Median time to symptom worsening, for all patients, was longer for the 250-mg/d group (4.1 months) than for the 500-mg/d group (2.8 months).
Generally, more patients showed an improvement in the pulmonary items of the LCS than in the nonpulmonary items. Improvements in shortness of breath, cough, and breathing were each seen in 78% of LCS responders, while appetite, weight loss, and clear thinking improved in 54% to 57% of LCS responders.
PFS and OS
Median PFS was 2.7 months (95% CI, 2.0 to 2.8) for the 250-mg/d group and 2.8 months (95% CI, 1.9 to 3.8) for the 500-mg/d group (Fig 4a), with 29% and 39% of patients, respectively, progression-free after 4 months of therapy. Median overall survival times were 7.6 months (95% CI, 5.3 to 10.1) and 8.0 months (95% CI 6.7 to 9.9) for the 250- and 500-mg/d groups, respectively (Fig 4b); 1-year survival rates were 35% and 29%, respectively.
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Fig 4. Kaplan-Meier plots showing (A) progression-free survival, (B) overall survival and (C) overall survival in patients with a complete or partial tumor response by dose.
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Tumor response was associated with improved OS. For patients with either CR or PR, the median OS was 13.3 months for 250-mg/d group and 10.6 months for the 500-mg/d group (Fig 4c).
QoL Assessed by TOI and FACT-L
Median baseline scores were 53 for TOI (range, 15–75) and 85 (range, 32–125) for FACT-L, indicating that this population had compromised QoL.
QoL improvement rate measured by TOI was 20.9% (95% CI, 11.9 to 32.6) for the 250-mg/d group and 17.8% (95% CI, 9.8 to 28.5) for the 500-mg/d group. QoL improvement rate measured by FACT-L was 23.9% (95% CI, 14.3 to 35.9) and 21.9% (95% CI, 13.1 to 33.1) at 250 and 500 mg/d, respectively. The median time to improvement (measured by TOI and FACT-L) for both doses was 29 days, the time of the first postbaseline assessment.
Efficacy in Japanese and Non-Japanese Patients
In this trial, the RR was higher for Japanese patients than non-Japanese patients (27.5% v 10.4%; odds ratio = 3.27; P = .0023). A population pharmacokinetic analysis of steady-state trough gefitinib plasma concentrations did not reveal any differences between Japanese and non-Japanese patients that might explain the difference in RR (data not shown). To further investigate this difference in RR observed between Japanese and non-Japanese patients, a planned multivariate logistic analysis was performed. Twenty-two baseline factors were evaluated independently to assess their value in predicting response. Using a 10% significance level, only seven factors were found to be predictive of response (baseline LCS, body mass index, PS, prior radiotherapy, histology, prior immuno/hormonal therapy, and sex). To ensure that only relevant baseline factors were retained in the multivariate model, the backward regression technique was employed at the 10% significance level. This resulted in only four factors being retained in the model: PS, sex, histology, and prior immuno/hormonal therapy (Table 4).
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Table 4. Final Adjusted Model of Prognostic Factors Associated With an Objective Response According to a Multivariate Analysis
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The final multivariate model, including all four significant baseline prognostic factors and the factor for ethnicity, resulted in a Japanese:non-Japanese odds ratio of 1.64 (95% CI, 0.71 to 3.93; P = .25), which is not considered to be statistically significant.
Safety and Tolerability
A total of 209 patients were evaluable for safety and tolerability. Most AEs seen in this trial were mild (CTC, G1 or G2), there was no evidence of cumulative toxicity, and most events were reversible. Drug-related AEs observed in more than 10% of patients on either dose are shown in Table 5. The first occurrence of most AEs was seen before the end of the first month of treatment. In the 250-mg/d group, 15.5% of patients had AEs requiring a short treatment interruption, and none required a dose reduction. At 500 mg/d, 28.3% of patients required a treatment interruption, and 10.4% required a dose reduction. The main reasons for dose interruptions were skin reactions, gastrointestinal disturbances, and elevated transaminases. Mean time on treatment was similar for the 250- and 500-mg/d groups, at 85.1 and 81.5 days, respectively, which corresponds to 97.8% and 93.8% of the total days on trial. Withdrawal due to drug-related AEs was 1.9% and 9.4% for patients receiving gefitinib doses at 250 and 500 mg/d, respectively. The main reasons for withdrawal mirrored reasons for drug interruption.
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Table 5. Patients With Drug-Related Adverse Events That Occurred in More Than 10% of Patients in Either Dose Group
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Of all the drug-related AEs reported, CTC G3 or G4 was seen in only 1.5% of patients receiving 250 mg/d and in 4.7% of those receiving 500 mg/d; no G4 drug-related AEs were reported at 250 mg/d. The most frequent drug-related G3 or G4 AEs included diarrhea, rash, and ALT elevation (Table 5). The AE profile and the incidence of G3 or G4 drug-related AEs were similar for the Japanese and non-Japanese populations.
Diarrhea could be controlled, if necessary, with antidiarrheal agents such as loperamide. Twenty-four percent of 250-mg/d patients and 43% of 500-mg/d patients took antipropulsives or antidiarrheal agents. Furthermore, diarrhea resolved in 84% (250 mg/d) and 83% (500 mg/d) of patients. Of these patients, resolution occurred during treatment (with or without dose reduction) or during temporary therapy interruption in 47.6% (250 mg/d) and 57.6% (500 mg/d) of patients, or following treatment cessation in 19.0% (250 mg/d) and 15.3% (500 mg/d). We did not record the exact time at which the event resolved in 33.3% of the 250-mg/d group and in 27.1% of the 500-mg/d group. Only one patient, receiving 500 mg/d, was withdrawn from the trial due to drug-related gastrointestinal disturbance (combination of G3 diarrhea, G3 nausea, and G2 vomiting).
Skin disorders, including rash, pruritus, dry skin, and acne, were generally mild (Table 5). Patients with rash also frequently reported other skin-related symptoms, including acne (10.6%), pruritus (45.5%), and dry skin (30.8%). In most patients, these skin disorders resolved either during treatment or temporary therapy interruption, or following treatment cessation. Two 500-mg/d patients withdrew from the trial due to skin disorders after 7 and 10 days of treatment (one with G3 rash; one with G1 rash). Concurrent rash and diarrhea was seen in 15.5% and 25.5% of patients receiving gefitinib at 250 and 500 mg/d, respectively.
Two patients experienced interstitial lung-disease–type events during the study (interstitial pneumonia and pneumonitis). Both patients were receiving 500 mg/d of gefitinib. One patient recovered from the event following withdrawal from treatment due to disease progression; in the other patient, the pneumonitis occurred 3 days after stopping gefitinib treatment because of severe fatigue, and was ongoing at the time of death due to disease progression 5 weeks later. A computed tomography scan for this patient showed progression of carcinomatous pleuritis. Both patients received antibiotics, steroids, and oxygen therapy.
Most patients had no deterioration in hepatic function during the trial, and occurrences of elevated levels of transaminases were generally G1 and asymptomatic. Four patients (three at 500 mg/d) were withdrawn from the trial due to G3 or G4 elevations in hepatic enzymes. No clinically significant deterioration in renal function was observed during the trial, even in patients who entered the trial with mild or moderate renal impairment. The incidence of cardiovascular events was low; seven patients (one at 250 mg/d; six at 500 mg/d) had G1 or G2 cardiovascular events. Two patients in the 250-mg/d group had a G3 drug-related AE (atrial fibrillation and bundle branch block), and one patient in the 500-mg/d group had G4 deep thrombophlebitis.
Ophthalmic monitoring did not reveal any significant drug-related abnormalities and no drug-related G3 or G4 events were reported. G1 or G2 drug-related ophthalmic AEs were reported in 43 patients (21%), but none of these events required withdrawal from therapy. These events included conjunctivitis, blepharitis, keratitis, eye pain, dry eyes, and corneal erosion.
No clinically significant changes in hematology parameters were observed during the trial; most patients experienced no changes from baseline in CTC grade for hemoglobin, platelets, or WBC values. The only drug-related G3 or G4 hematologic AE reported was anemia, which was seen in three 500-mg/d patients (G3, one patient; G4, two patients), but no patients were withdrawn due to anemia.
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DISCUSSION
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This multicenter, randomized, double-blind, parallel-group trial conducted in Europe, Australia, South Africa, and Japan evaluated the efficacy and safety of daily oral doses of 250 and 500 mg of gefitinib in patients with locally advanced or metastatic NSCLC who had previously received either one, or a maximum of two, chemotherapy regimens (at least one of which had contained platinum). The major aim of the randomization was to identify the optimal dose for patients in this setting. In 103 patients treated with gefitinib at 250 mg/d, the RR was 18.4%, with a median PFS of 2.7 months and a median OS of 7.6 months, suggesting that gefitinib is an effective treatment for previously treated patients with advanced NSCLC. The RR was similar for the 500-mg dose and for patients receiving gefitinib as second- and third-line treatment.
With respect to safety, drug-related AEs at both doses were generally mild (G1 or G2), consisting mainly of skin reactions and diarrhea, but the incidence of AEs, dose modifications, and withdrawals was lower for 250-mg/d group than for 500-mg/d group. Additionally, gefitinib was not associated with common conventional chemotherapy AEs such as neutropenia, thrombocytopenia, or neuropathy. Less than 1% of patients experienced interstitial lung-disease–type events during the study. The data from this trial suggest that treatment with gefitinib at 250 mg/d does not require any special clinical or laboratory monitoring beyond the usual standards of care in this patient population.
Overall, 250 mg/d was as effective as, and better tolerated than, 500 mg/d, and is thus the recommended dose for patients with NSCLC who have previously received platinum-based chemotherapy. This dissociation of the efficacy and safety dose-response relationships was predicted for molecularly targeted anticancer agents such as gefitinib.22
Following inevitable first progression or recurrence after first-line chemotherapy, the current therapeutic option for patients with advanced NSCLC is additional chemotherapy. In the second-line setting, numerous phase II trials of one or more chemotherapy agents have reported widely varying RRs and little or no data concerning other efficacy end points.23 The notable exception is docetaxel, the only approved chemotherapy agent for treatment of previously treated patients and the only agent for which phase III data exists in a large number of patients with prior platinum therapy. In the first of two randomized phase III trials, median survival with docetaxel was significantly better than the supportive care arm (7.0 v 4.6 months; P = .047).7 The RR for the 55 patients who received docetaxel at 75 mg/m2 was 5.5%, and the overall disease control rate was 52.8%. In the second trial, the median survival with 75 mg/m2 of docetaxel was 5.7 months, the RR was 6.7%, and the disease control rate was 42.7%.24 These trials also demonstrated that docetaxel has a positive impact on QoL.25
A key therapeutic aim in patients with NSCLC is to palliate disease-related symptoms without compromising overall QoL. Patients with progressive NSCLC who have been failed by previous chemotherapy have an extremely poor prognosis and often exhibit severe symptoms. The patient population in this study was symptomatic, with median baseline LCS and TOI scores of 18.0 and 53.0, respectively. This is comparable with a randomized trial comparing three first-line chemotherapeutic regimens in patients with advanced NSCLC, which reported mean baseline LCS and TOI scores of 18.7 and 56.4, respectively.20 Our study provided a unique demonstration of clinically significant improvement in disease-related symptoms, which was documented both in patients with tumor regression and in those with stable disease. The rate of disease-related symptom improvement was high, with approximately 40% of the patients in the 250-mg/d group experiencing improvement for at least 1 month. The median time to symptom improvement was short, occurring within 8 days, and QoL improvements also appeared rapidly.
The statistically significant difference in RR between Japanese and non-Japanese patients could not be explained on the basis of pharmacokinetic differences in the two populations. However, it was possible to identify baseline prognostic factors that accounted for these results (PS of 0–1, receipt of prior immuno/hormonal treatment, female sex, and adenocarcinoma histology). After accounting for baseline imbalances between the populations, the odds ratio for ethnicity was 1.64, which is not considered to be statistically significant (P = .25). Performance status and sex have been previously identified as prognostic factors for RR and survival following first-line chemotherapy in individuals with NSCLC.23 In this study, the better outcome in women could not be accounted for by sex differences in pharmacokinetic parameters. It is interesting that adenocarcinoma is a prognostic factor, given that EGFR is more frequently expressed in squamous cell carcinoma26; it may be that the relatively slow growth of adenocarcinoma cells renders them more sensitive to gefitinib, or there might be an unknown factor at the protein level that determines sensitivity to gefitinib rather than the level of EGFR expression. We do not yet know whether the EGFR status of tumors influences the efficacy of gefitinib. However, tissue samples have been retained to assess EGFR status by immunohistochemistry, and analysis of these samples is underway.
A second phase II trial of gefitinib monotherapy for the treatment of advanced NSCLC in patients who have received at least two previous chemotherapy agents, including platinum and docetaxel, has been completed and confirms the activity of gefitinib in heavily pretreated patients.27
In conclusion, oral gefitinib at 250 or 500 mg/d provides clinically significant durable antitumor activity, accompanied by rapid, clinically meaningful symptom relief and improvements in QoL as second- and third-line treatment in patients with advanced NSCLC who have received previous platinum-based therapy. The 250-mg/d dose of gefitinib has a more favorable safety profile and better tolerability than the 500-mg/d dose and is, therefore, the recommended dose in this clinical setting. The data from this multi-institutional, randomized phase II trial suggest that oral gefitinib is an important, novel treatment option for patients with previously treated advanced NSCLC.
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APPENDIX
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The following individuals are the principal investigators (PIs) and coinvestigators at cancer centers participating in this trial: J. Baselga (PI), E. Felip, Vall d’Hebron University Hospital, R. Rosell (PI), J.M. Sanchez, J.L. Manzano, Hospital Universitario Germans, Barcelona; and J.L.G. Larriba (PI), R. Alfonso, J.C. Camara, Hospital Clinico S. Carlos de Madrid, Madrid, Spain. M. Green (PI), J.C. Ding, S. Fan, Western Hospital, D. Rischin (PI), G. McArthur, L. Mileshkin, M. Michael, J. Zalcberg, C. Scott, L. Sullivan, M. Grossi, Peter MacCallum Cancer Institute, M. Rosenthal (PI), R. Basser, M. Green, Royal Melbourne Hospital, Melbourne; and P. Mitchell (PI), R. de Boer, Austin & Repatriation Medical Centre, Heidelberg, Australia. L. Dirix (PI), Medicine Institute St. Augustinus, Wilrijk; and J. Vansteenkiste (PI), K. Nackaerts, University Hospital Gasthuisberg, Leuven, Belgium. R. Callaghan (PI), L. Jooste, R. De Bruyne, S. Cullis, Hopelands Cancer Centre, Durban; B. Rapaport (PI), Medical Oncology Centre of Rosebank, Saxonworld; P. Ruff (PI), D. Moodley, Johannesburg Hospital, Parktown; and C. Slabber (PI), R.W. Eek, M.R. Chasen, G. Cohen, Mary Potter Oncology Centre, Pretoria, South Africa. B. Milleron (PI), C. Epaud, M.A. Massiani, J. Cadranel, Tenon University Hospital, Paris; J.Y. Douillard (PI), V. Barbarot, C.R.L.C.C. Rene Gauducheau, Saint-Herblain; D. Moro-Sibilot (PI), V. Frappat, G. Orliaguet, Michallon Hospital, Grenoble; and J.L. Pujol (PI), X. Quantin, D. Choma, Hopital Arnaud de Villeneuve, Montpellier, France. U. Gatzemeier (PI), G. Groth, Krankenhaus Grosshansdorf, Grosshansdorf; E. Kaukel (PI), G. Koschel, M. Eichler, Krankenhaus Harburg, Hamburg; and C. Manegold (PI), E. Buchholz, K. Schott, D. Wagner-Hug, Thoraxklinik, Heidelberg, Germany. G. Giaccone (PI), E. Smit, H. Smit, K. Hoekman, Academic Hospital Free University, Amsterdam, the Netherlands. S. Casinu (PI), S. Salvagni, L. Biscari, V. Franciosi, G. Vasini, University Hospital, Parma; A. Santoro (PI), R. Cavina, H. Parra, Istituto Clinico Humanitas, Rozzano-Milano; and G. Scagliotti (PI), G. Selvaggi, S. Novello, University of Turin, Orbassano, Italy. A. Yokoyama (PI), T. Shinbo, Y. Tsukada, M. Makino, K. Nanba, Niigata Cancer Center Hospital, Niigata, Japan; Dr H Saka (PI), Dr M Oki, Dr A Kumazawa, Dr C Sako, Dr H Hirose, Dr Y Kamiya, Nagoya University School of Medicine, and T. Sugiura (PI), T. Hida, K. Yoshida, K. Kato, Aichi Cancer Center Hospital, Aichi; I. Takata (PI), K. Eguchi, Y. Segawa, K. Fujiwara, Y. Tokuda, N. Seki, H. Shikata, N. Hashimoto, National Shikoku Cancer Center, Matsuyama; K. Kiura (PI), H. Ueoka, A. Hiraki, T. Kishino, Y. Emori, T. Matsuo, Okayama University Medical School, Okayama; K. Noda (PI), F. Oshita, I. Nomura, K. Yamada, M. Ikehara, K. Tsukahara, N. Kouno, K. Amano, Kanagawa Cancer Center, and K. Watanabe (PI), H. Kunikane, H. Okamoto, A. Nagatomo, H. Aono, H. Miyata, Yokohama Municipal Citizen’s Hospital, Yokohama; K. Nakagawa (PI), N. Yamamoto, H. Uejima, T. Komiya, G. Asai, A. Moriyama, J. Tsurutani, K. Akiyama, S. Tsukiyama, M. Fukuda, T. Hibino, M. Fukuoka, K. Yonesaka, T. Kurata, K. Tamura, Kinki University School of Medicine, K. Takeda (PI), S. Negoro, N. Takifuji, K. Terakawa, M. Miyazaki, M. Sumitani, Y. Ichimaru, H. Mori, S. Yu, T. Sugiura, Osaka City General Hospital, M. Takada (PI), T. Yana, T. Shimizu, F. Yamagami, H. Kaneda, T. Nishino, H. Shikata, Y. Morita, Y. Kuzumoto, T. Matsuyama, Osaka City University Medical School, K. Matsui (PI), T. Hirashima, T. Nitta, Y. Ogata, M. Kobayashi, Y. Takada, T. Sasabe, T. Kawamura, H. Bando, Osaka Prefectural Habikino Hospital, S. Kudoh (PI), H. Kamoi, T. Okamoto, N. Yoshimura, S. Shiraishi, T. Mukouhara, S. Yamauchi, K. Asai, A. Obana, M. Matsumoto, T. Kohno, T. Yasunari, Osaka City University School of Medicine, and F. Imamura (PI), K. Ueno, S. Yamamoto, I. Nagatomo, K. Karashima, S. Fujioka, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka; N. Katakami (PI), M. Okazaki, M. Hasegawa, A. Ikeda, T. Nishimura, S. Fujita, C. Nishio, K. Miyamoto, Kobe University Hospital, Hyougo; S. Yano (PI), S. Sone, Y. Nishioka, M. Azuma, A. Yamamoto, T. Kanematsu, T. Tajika, K. Shinomiya, Tokushima University School of Medicine, Tokushima; T. Horai (PI), M. Nishio, A. Karato, H. Tuji, Japanese Foundation for Cancer Research, and T. Tamura (PI), H. Kunito, I. Sekine, Y. Ohe, N. Yamamoto, A. Kaneko, K. Horie, H. Nokihara, T. Shimoyama, H. Murakami, N. Yamazaki, National Cancer Center, Central Hospital, Tokyo; T. Sawa (PI), T. Yoshida, M. Sawada, T. Ishiguro, Y. Kono, Gifu Citizens Hospital, Gifu; and Y. Nishiwaki (PI), R. Kakinuma, K. Kubota, T. Matsumoto, H. Omatsu, K. Goto, S. Niho, M. Nomura, Y. Minegishi, K. Araki, T. Mizoguchi, National Cancer Center, East Hospital, Chiba, Japan.
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ACKNOWLEDGMENTS
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We would like to acknowledge the assistance of the Clinical Study Leader, Sally Sambrook; the Clinical Team Leader, Yuhiko Nogi; the Clinical Research Leader, Sue Hunter; and the Clinical Strategy Manager, Masaru Hirose.
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NOTES
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The authors wish to disclose the following conflicts of interest statement: José Baselga has been in receipt of a research grant from AstraZeneca and honoraria to attend advisory boards and to give talks on ZD1839; Johan Vansteenkiste has received honoraria from AstraZeneca to attend advisory boards; Jean Yves Douillard has received honoraria for participating in advisory boards or symposia; Giuseppe Giaccone has received honoraria and research grants; and Danny Rischin has been in receipt of honoraria and travel grants from AstraZeneca. Steven Averbuch, Angela Macleod, Andrea Feyereislova, and Rui-Ping Dong were employed by AstraZeneca at the time of study completion, and as such, may hold stock in the company. All other authors have nothing to declare.
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Submitted October 4, 2002;
accepted January 28, 2002.
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TOP
ABSTRACT
INTRODUCTION
