Published online before print
September 27, 2006, 10.1183/09031936.00050706
Eur Respir J 2007; 29:128-133
Copyright ©ERS Journals Ltd 2007
Gefitinib monotherapy in advanced nonsmall cell lung cancer: a large Western community implementation study
R. van Puijenbroek1,
L. Bosquée2,
A-P. Meert3,
D. Schallier4,
J-C. Goeminne5,
G. Tits6,
P. Collard7,
K. Nackaerts1,
J-L. Canon8,
F. Duplaquet9,
D. Galdermans10,
P. Germonpré11,
M-A. Azerad12,
G. Vandenhoven12,
J. De Greve4 and
J. Vansteenkiste1
1 Univ. Hospital, Catholic University, Leuven, 2 Citadelle Hospital, Liège, 3 Jules Bordet Institute, 4 University Hospital VUB, 7 Cliniques Universitaires St.-Luc, and 12 Astra Zeneca Medical, Brussels, 5 St-Elisabeth Hospital, Namur, 6 St-Andries Hospital, Tielt, 8 Notre Dame Hospital, Charleroi, 9 Univ. Hospital UCL, Yvoir, 10 Middelheim Hospital, and 11 Univ. Hospital UIA, Antwerp, Belgium.
CORRESPONDENCE: J. Vansteenkiste, Respiratory Oncology Unit (Pneumology), University Hospital Gasthuisberg, Herestraat 49, 3000 Leuven, Belgium. Fax: 32 16346803. E-mail: johan.vansteenkiste{at}uz.kuleuven.ac.be
Keywords: Community implementation study, epidermal growth factor, expanded access, gefitinib, nonsmall cell lung cancer, treatment outcome
Received: April 12, 2006
Accepted August 29, 2006
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ABSTRACT
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Epidermal growth factor receptor tyrosine kinase inhibitors represent a new treatment option for patients with advanced nonsmall cell lung cancer (NSCLC). This retrospective study examined to what extent previous clinical trial experience matches large-scale Western community implementation of this treatment.
In the Belgian expanded access programme, the data from 513 patients with advanced or metastatic NSCLC, not suitable for further chemotherapy and receiving oral gefitinib 250 mg·day-1 until disease progression, death or unacceptable toxicity, were analysed.
The median (range) duration of gefitinib treatment was 2.3 months (0.0–32.7). Its use was predominantly in second- or third-line treatment. The overall response and disease control rates were 8.9 and 41.2%, respectively. In univariate analysis, response was more common in females and never-smokers. In multivariate analysis, female sex was the only significant predictive factor (odds ratio (OR) (95% confidence interval (CI)) 0.329 (0.129–0.839)). Symptom improvement was reported in 108 patients of whom 32 (29.6%) had an objective response, 66 (61.1%) experienced disease stabilisation and 10 (9.3%) progressed. Gefitinib was well tolerated; only 7.8% of the patients reported grade 3 or 4 toxicity. The overall median survival was 4.7 months, with a 1-yr survival rate of 21%. Survival was strongly influenced by a better performance status (PS) (good PS: hazard ratio (HR) (95%CI) 0.110 (0.077–0.157)) and adenocarcinoma with bronchioloalveolar carcinoma features histology (HR (95%CI) 0.483 (0.279–0.834)).
In conclusion, the activity of gefitinib was confirmed in the present large Western community implementation study. Response, present in a small subgroup, led to a rewarding survival and could be predicted by sex only. Baseline performance status and adenocarcinoma with bronchioloalveolar carcinoma features histology were significant factors for survival.
The treatment of advanced nonsmall cell lung cancer (NSCLC) has improved over the past decade. Cisplatin-based chemotherapy improves the outcome of patients with early 1 or locally advanced NSCLC 2. In metastatic disease, modern regimens combining platinum with gemcitabine or taxanes have brought the 1-yr survival rate from 15 to 30%. However, a therapeutic plateau has been reached with the current chemotherapeutic options. Furthermore, better options for patients who relapse after first- and second-line chemotherapy are needed 3. Consequently, targeted therapy gained a central place in current cancer therapeutics development. The most striking example is the success of imatinib in the treatment of gastrointestinal stromal tumours 4. As NSCLC is characterised by frequent expression of the epidermal growth factor receptor (EGFR), this target was studied extensively. Based on the results of two randomised phase II studies (Iressa Dose Evaluation in Advanced Lung Cancer (IDEAL) 1 and 2) showing encouraging response and symptom improvement rates in heavily pre-treated patients, the EGFR tyrosine kinase inhibitor (TKI) gefitinib became the first available targeted therapy for the treatment of NSCLC 5, 6. Gefitinib was approved for the treatment of relapsed NSCLC in several countries, including Japan and the USA. In the meanwhile, no additional benefit could be demonstrated when gefitinib was added to standard first-line chemotherapy in the Iressa NSCLC Trial Assessing Combination Treatment (INTACT) studies 7, 8. In the phase III Iressa Survival Evaluation in Lung Cancer (ISEL) study in patients failing after previous chemotherapy, gefitinib improved survival compared to best supportive care alone. However, this difference did not reach significance except in pre-defined subgroups, such as never-smokers or Asian patients 9.
In a worldwide Expanded Access Program (EAP), patients with advanced NSCLC and no alternative therapeutic options were able to receive gefitinib treatment. As a variable degree of selection is always present in the context of prospective clinical trials, it is important to study the applicability of their results in community settings. The present study represents the retrospective analysis of the patients enrolled in the EAP in Belgium. The purpose of the analysis is to examine the response and outcome with gefitinib and the tolerability within the general community setting as well as to identify clinical parameters that may predict for response or survival. In an ancillary study, a set of genetic parameters that could predict gefitinib sensitivity will be analysed and reported separately.
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PATIENTS AND METHODS
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Cohort assembly
Patient data were retrieved from the Belgian EAP, which involved a total of 1,464 patients enrolled between January 2001 and December 2004. All patients with proven advanced NSCLC failing previous chemotherapy or without alternative therapeutic options were able to receive gefitinib 250 mg·day-1 until disease progression, death or unacceptable toxicity occurred. Inherent to this type of study, response assessment was not prospectively structured according to, for example, Response Evaluation Criteria in Solid Tumours (RECIST) parameters, but performed at each centre according to local standards. In general, a first evaluation of response with clinical factors 10, chest radiography and/or computed tomography scan took place after 4–6 weeks of treatment. Symptom improvement (SI) was evaluated according to the clinical judgement of the treating physician. All participating patients gave written informed consent. All centres that had 
10 patients in the EAP participated in the present study, except for one refusal in a centre with 14 cases. A standardised questionnaire listing data on demographics, tolerability, response, symptom improvement and outcome was used to sample the data. Baseline assessment included smoking history, World Health Organization (WHO) performance status (PS), tumour assessment and previous local therapy (surgery or radiotherapy). Detailed information about previous chemotherapy was included, i.e. number of lines, drugs administered, duration of treatment, treatment-free intervals and best objective response to each line.
Statistics
Descriptive data are presented as median (range). The relationship between patients' characteristics and likelihood of response, disease control (i.e. response or stabilisation) or symptom improvement were tested using a Chi-squared test in the univariate analysis and logistic regression in the multivariate analysis. The variables of interest were sex, performance status, smoking history, histology and number of lines of prior chemotherapy. Overall survival was defined as the period between the start of gefitinib treatment and the date of last follow-up for censored cases or date of death. For survival, the same set of variables was studied. The relationship with survival was studied with the Kaplan–Meier analysis and log-rank test and with Cox regression for multivariate analysis. A p-value <0.05 was considered to be statistically significant.
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RESULTS
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Data from 513 patients were retrieved from different academic (six centres, 267 patients) and nonacademic (five centres, 246 patients) hospitals.
The patients' demographics are listed in table 1
. Male and stage IV subgroups were 
75% of the total number of patients each. There were 40 (7.8%) never-smokers and 34 (6.7%) patients with adenocarcinoma with bronchioloalveolar carcinoma features (AD/BAC). Almost 60% of the patients had received 2 lines of chemotherapy before entering the EAP with gefitinib. This chemotherapy mostly consisted of platinum (81.5%), gemcitabine (71.4%) or vinorelbine (30.2%), and a taxane (50.7%), as currently accepted first- and second-line treatment. Gefitinib was used as primary treatment in patients non amenable to chemotherapy due to low PS, comorbidity or refusal. The median (range) duration of gefitinib treatment was 2.3 months (0.0–32.7) in the total group.
The overall observed response rate (RR) was 8.9%, with four complete responders (table 2). The median (range) duration of intake of gefitinib in responders was 8.1 months (1.9–25.4), with 13 patients still taking gefitinib at the time of analysis. The RR was significantly higher in females compared with males (16.2 versus 6.2%, p = 0.002) and lifetime never-smokers compared with ever-smokers (21.8 versus 8.0%, p = 0.009).
The overall observed disease control rate (DCR) was 41.2%. The median (range) duration of intake of gefitinib in these patients was 6.8 months (0.6–32.7) with 21 patients still taking gefitinib at the time of analysis. DCR correlated significantly with a better PS (good versus intermediate versus poor: 55.7 versus 36.7 versus 12.5%; p<0.0001), number of previous chemotherapy regimens (none versus one versus two: 60.0 versus 48.1 versus 34.9%; p = 0.004) and with AD/BAC histology compared to non-AD/BAC histology (60.0 versus 39.9%, p = 0.049).
In the multivariate analysis, likelihood of response was significantly determined by female sex (odds ratio (OR) (95% confidence interval (CI)) 0.329 (0.129–0.839), p = 0.020). For disease control the only significant factor was a good PS (OR (95%CI) 0.105 (0.035–0.320), p<0.0001). A never-smoking history was nonpredictive.
In patients for whom sufficient symptom data were available (unknown in 118 patients), 29% (108 patients) experienced an improvement in overall symptoms. Of these, 32 (29.6%) had an objective response, 66 (61.1%) experienced disease stabilisation and 10 (9.3%) progressed. In univariate analysis, there was a statistically significant association between SI and PS (good versus intermediate versus poor: 40.3 versus 22.5 versus 7.5%; p<0.0001) and AD/BAC histology (AD/BAC versus non-AD/BAC, 73.7 versus 26.8%; p = 0.048), but not with sex or smoking status.
The median overall survival time (MST) after the start of treatment with gefitinib was 4.7 months, with a 1-yr survival rate (1YSR) of 21% (table 3). Figure 1 shows the Kaplan–Meier estimates of overall survival comparing patients with good, intermediate or poor PS (p<0.0001). Other factors associated with better survival rates were AD/BAC histology (p = 0.033) (fig. 2) and the number of prior chemotherapy treatments (p = 0.013). In the multivariate Cox regression, better PS (good PS: HR (95%CI) 0.110 (0.077–0.157), p<0.0001; and intermediate PS: HR (95%CI) 0.283 (0.202–0.396), p<0.0001) and AD/BAC histology (HR (95%CI) 0.483 (0.279–0.834), p = 0.009) remained significant predictive factors for survival.
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Fig. 1— Survival according to the performance status (PS) at the start of gefitinib treatment. ——: PS 0–1; ------: PS 2; ········: PS 3–4.
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Fig. 2— Survival according to adenocarcinoma with bronchioloalveolar features (AD/BAC; ——) or non-AD/BAC (········) histology.
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The favourable tolerability of gefitinib was confirmed: only 7.8% of the patients were reported with grade 3 or 4 toxicity. A serious adverse event of pulmonary nature was reported in eight of the 513 patients. Five of these belonged to another category: cardiogenic pulmonary oedema (n = 1), diffuse progression of tumour with bronchioloalveolar features (n = 1), infectious pneumonia (n = 2) and infectious pneumonia plus pulmonary embolism (n = 1). Three instances of interstitial lung disease (ILD) were reported. One of these was unlikely to be related to gefitinib, as the ILD occurred 13 months after discontinuation of gefitinib. Two others were probably related, occurring 31 and 33 days after the start of gefitinib treatment, respectively. In both patients, other causes of ILD were ruled out. Both improved with cessation of gefitinib and administration of corticosteroids.
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DISCUSSION
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This retrospective analysis of the treatment with gefitinib for advanced NSCLC in a mixed academic and nonacademic setting in the Belgian EAP demonstrated clear antitumour activity (RR 8.9%; DCR 41.2%) in the absence of major toxicity (grade 3 or 4 toxicity 7.8%). The median duration of intake of gefitinib was 8.1 months in responding patients and 6.8 months in patients with disease stabilisation. Although the present authors do not really have the exact time to progression based on rigorous radiological follow-up, the results suggest a clinically meaningful duration of the effect of gefitinib in many patients. Symptom improvement was reported in 29.0% of the patients. As a whole, the findings in this large Western community implementation study demonstrate that the findings from previous prospective clinical trials 5, 6 are reproducible in a probably less selected group of patients coming from daily practice.
In the multivariate analysis, only female sex could be retained as a predictive factor for activity, but not histology or smoking status. Based on prospective trials and retrospective series, Asian origin, never-smoking status, adenocarcinoma histology and female sex are the most often reported predictors of response 5, 11–15. Ethnicity was not a factor in the present series, as all patients were Caucasians. The never-smoking status of lung cancer patients is probably the strongest indicator of activity in Western populations 9, 11, 12, 15, 16. This factor was significant in the current univariate analysis (p = 0.009), but was not withheld in the multivariate analysis probably due to the lower number of known never-smokers in the series or due to overlap with other clinical factors. The RR was similar in patients with adenocarcinoma compared with nonadenocarcinoma (9.4 versus 8.4%) and AD/BAC compared with non-AD/BAC histology (12.0 versus 8.7%). This is in contrast with most other studies, where adenocarcinoma histology, especially the AD/BAC subtype, is usually associated with higher likelihood of response 11–17. The fact that different centres and, as such, different pathologists participated in the present study may be a factor in this apparent discrepancy. Nevertheless, responses in patients with squamous cell carcinoma were also reported in a recent large phase III study with the EGFR-TKI erlotinib 16.
A correlation was also found between PS and activity of gefitinib. As patients with a very low performance status (3 or 4) are in general not considered for chemotherapy, the issue has been raised whether this group could benefit from better-tolerated targeted therapies like gefitinib. These patients were, however, excluded from the prospective trials with gefitinib. The activity of gefitinib was poor in the present low PS population, suggesting that they are unlikely to benefit from this therapy, but as there was no comparator arm in the present study, it is not possible to ascertain that there would not be a benefit over best supportive care alone in such patients.
The MST of the total group was 4.7 months after the start of treatment with gefitinib, with a 1YSR of 21%. This is somewhat inferior to the survival data in the IDEAL studies 5, 6, probably due to a lower degree of patient selection in the present implementation study, as can be illustrated by the inclusion of 73 patients with very poor PS. This subgroup performed very badly, with a MST of only 1.1 month. The importance of PS for outcome has been reported by others as well 11, 14, 17, 18. Apart from PS, AD/BAC histology was retained as a predictor of survival in the multivariate analysis. The longer MST of the patients with AD/BAC in the present series is probably an indicator of the more indolent course of this special type of NSCLC 19.
A favourable outcome in a subpopulation of NSCLC patients who respond to gefitinib was observed. Some responding patients experienced long-term benefit of the treatment, as can be suggested from the median duration of gefitinib treatment of 8.1 months in responders, up to a total of >2 yrs in a few patients. It is, however, urgently needed to have unequivocal predictors of activity of this important targeted agent for NSCLC. As it is obvious from the present community series and the experience of others, the "clinical" predictors of response are not well established in Western populations, with the exception of a never-smoking status in some series 9, 16. Better and more targeted use of agents such as gefitinib is clearly needed to bring this breakthrough in the treatment of NSCLC to those patients who really benefit in a way that can be afforded by the health security systems. Increasing the understanding of the mechanism of action of these agents and deriving an unequivocal and specific predictive test from this knowledge is the way forward. At the present moment, such a test is not available for clinical practice. Expression of EGFR on the cell surface, measured by grading immunohistochemical staining with an EGFR antibody, is in general poorly predictive for a response 20, 21. A frequent occurrence of EGFR domain mutations, reported in responders to EGFR-TKIs 22, 23, could not be confirmed in a recent phase III study 16. The presence of a high EGFR gene copy number identified by fluorescence in situ hybridisation may become the most promising molecular predictor for gefitinib efficacy in NSCLC 24. Further molecular analysis in the group of patients from the present series is ongoing.
The strengths of the present study are: the fact that it represents a large sample of patients of both university-affiliated and community hospitals from across the country, the collection of data during a defined time window and the use of a standardised data collection tool. The present study also has several potential limitations. The inclusion of some chemo-naive patients in the EAP for reasons of poor PS or comorbidity was allowed, despite the fact that this did not correspond to standard treatment guidelines. Less structured or less detailed documentation of patient data in the medical record is inherent to all retrospective chart audits, like the present implementation study.
Finally, it was not the aim of the present authors to measure safety and toxicity in detail, as this had already been performed in prospective series 5–8. The data query sheet used only asked for the severe toxicity (grade 3 or 4 according to the National Cancer Institute Common Toxicity Criteria) occurring during gefitinib treatment. No further information on lower grade toxicity was asked in order to avoid the use of a too complex sheet for several nonacademic centres. One side-effect, drug-induced ILD is, however, of particular concern due to its potential severity, especially in Asian patients 25. Most probably, the incidence in Western populations is only slightly elevated. In a large phase III study, an incidence of ILD of 1.5% for patients taking gefitinib 250 mg·day-1 and 0.9% for patients taking placebo was reported, a difference of 0.6% 8. In another phase III study, the overall incidence of ILD-type events was <1% 7. In the present series, which is one of the largest EAPs with a pure Caucasian population, no serial pulmonary function tests were in place, but clinically relevant ILD probably related to gefitinib could be withheld in two instances (0.4%). Both patients recovered with cessation of the drug and corticosteroid medication.
In summary, the present large Western community implementation study of gefitinib for advanced nonsmall cell lung cancer confirmed the good tolerability of this agent. Response, present in a subpopulation, led to very rewarding survival outcomes. Clinically meaningful symptom improvement was linked to disease response and disease stabilisation. Response could be predicted by sex only. Better predictive tests of activity of gefitinib are urgently needed to allow us to offer this therapy in a true targeted approach to those nonsmall cell lung cancer patients who would really benefit from this therapy while keeping the expenses for society at an acceptable level.
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ACKNOWLEDGEMENTS
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The authors would like to thank all colleagues who contributed to the analysis: L. Bosquée, J-L. Canon, P. Collard, F. Duplaquet, J. De Greve, D. Galdermans, P. Germonpré, J-C. Goeminne, A-P. Meert, K. Nackaerts, T. Pieters, D. Schallier, G. Tits and J. Vansteenkiste. The authors would also like to thank Astra Zeneca (Brussels, Belgium) for providing the EAP and for their help in the acquisition of the database (K. Geeroms) and all the patients who participated in the EAP.
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ABSTRACT
PATIENTS AND METHODS
