This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Crinò, L. Articles by Cullen, M. Search for Related Content PubMed PubMed Citation Articles by Crinò, L. Articles by Cullen, M. Social Bookmarking                            What's this?

Gefitinib Versus Vinorelbine in Chemotherapy-Naïve Elderly Patients With Advanced Non–Small-Cell Lung Cancer (INVITE): A Randomized, Phase II Study

Lucio Crinò, Federico Cappuzzo, Petr Zatloukal, Martin Reck, Milos Pesek, Joyce C. Thompson, Hugo E.R. Ford, Fred R. Hirsch, Marileila Varella-Garcia, Serban Ghiorghiu, Emma L. Duffield, Alison A. Armour, Georgina Speake, Michael Cullen

From the Department of Medical Oncology, Perugia Hospital, Perugia; and Instituto Clinico Humanitas Istituto di Recovero e Cura a Carattere Scientifico, Rozzano, Italy; Third Faculty of Medicine, Charles University, Faculty Hospital Bulovka and Postgraduate Medical Institute, Prague; and Charles University Medical Faculty, Plzen, Czech Republic; Hospital Grobhansdorf, Groβhansdorf, Germany; Birmingham Heartlands Hospital; Queen Elizabeth Hospital, Birmingham; Cambridge University Hospitals National Health Service Foundation Trust, Cambridge; and AstraZeneca, Macclesfield, Cheshire, United Kingdom; and University of Colorado Cancer Center, Aurora, CO

Corresponding author: Lucio Crinò, MD, Department of Medical Oncology, Perugia Hospital, S Andrea delle Fratte, 06156 Perugia, Italy; e-mail: lcrino{at}unipg.it

	ABSTRACT

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
Purpose This phase II, open-label, parallel-group study compared gefitinib with vinorelbine in chemotherapy-naïve elderly patients with advanced non–small-cell lung cancer (NSCLC).

Methods Chemotherapy-naïve patients (age 70 years) were randomly assigned to gefitinib (250 mg/d orally) or vinorelbine (30 mg/m² infusion on days 1 and 8 of a 21-day cycle). The primary end point was progression-free survival (PFS). Secondary end points were overall survival (OS), objective response rate (ORR), quality of life (QOL), pulmonary symptom improvement (PSI), and tolerability. Exploratory end points included epidermal growth factor receptor (EGFR) gene copy number by fluorescent in situ hybridization (FISH).

Results Patients were randomly assigned to gefitinib (n = 97) or to vinorelbine (n = 99). Hazard ratios (HR; gefitinib v vinorelbine) were 1.19 (95% CI, 0.85 to 1.65) for PFS and 0.98 (95% CI, 0.66 to 1.47) for OS. ORR and disease control rates were 3.1% (95% CI, 0.6 to 8.8) and 43.3% (for gefitinib) and 5.1% (95% CI, 1.7 to 11.4) and 53.5% (for vinorelbine), respectively. Overall QOL improvement and PSI rates were 24.3% and 36.6% (for gefitinib) and 10.9% and 31.0% (for vinorelbine), respectively. In the 54 patients who were EGFR FISH-positive, HRs were 3.13 (95% CI, 1.45 to 6.76) for PFS and 2.88 (95% CI, 1.21 to 6.83) for OS. There were fewer treatment-related grade 3 to 5 adverse events with gefitinib (12.8%) than with vinorelbine (41.7%).

Conclusion There was no statistical difference between gefitinib and vinorelbine in efficacy in chemotherapy-naïve, unselected elderly patients with advanced NSCLC, but there was better tolerability with gefitinib. Individuals who were EGFR FISH-positive benefited more from vinorelbine than from gefitinib; this unexpected finding requires further study.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
Non–small-cell lung cancer (NSCLC) accounts for 80% of all lung cancers,¹ and approximately 30% to 40%^1,2 of patients diagnosed are aged 70 years or older. The median age of patients with newly diagnosed NSCLC approaches 68 years.³ Although platinum-based chemotherapy can be administered safely to selected patients older than 70 years without relevant comorbidity and good performance status,⁴ elderly patients are less likely than younger patients to receive standard two-drug combinations,⁵ and monotherapy with vinorelbine or gemcitabine often is offered in clinical practice to individuals with advanced disease.⁵ Such therapy produces modest results, with response rates of 14% to 18% and median overall survival of 7 to 8 months reported for vinorelbine in chemotherapy-naïve patients,^5,6 may cause hematologic and neurologic adverse effects (AEs), and may require intravenous administration.⁵

In recent years, new agents that interfere with a specific target involved in cancer proliferation have been developed, including small molecules that inhibit the tyrosine kinase activity of the epidermal growth factor receptor (EGFR-TKI). The oral EGFR-TKI gefitinib (ZD1839, Iressa, AstraZeneca, Macclesfield, United Kingdom) demonstrated promising activity and manageable toxicity in phase II studies.^7,8 In these studies, which were conducted in patients previously exposed to chemotherapy and without any clinical or biologic selection, gefitinib produced a response rate of up to 18%, a median progression-free survival (PFS) of approximately 3 months, and a median survival of approximately 7 months.^7,8 These results seemed similar to those produced with the single agent vinorelbine,^5,6 which suggests that an oral drug could represent a reasonable alternative to intravenous chemotherapy in elderly patients who have advanced NSCLC. Recently, clinical and biologic predictors have been identified that may provide an indication of EGFR-TKI sensitivity.^9-12 A history of never smoking, female sex, adenocarcinoma histology, and Asian ethnicity are considered the most relevant clinical predictors, whereas the presence of activating EGFR gene mutations or increased EGFR gene copy number may be the most relevant biologic factors associated with improved response and survival.^9,11

The results obtained in unselected patients and the absence of any biologic predictor of TKI sensitivity at the time of study design led us to design this randomized, phase II study to explore gefitinib sensitivity in untreated elderly patients who have NSCLC and who were not selected on the basis of any biologic or clinical characteristics.

	METHODS

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
Study Design and Procedures
This phase II, randomized, open-label, multicenter, parallel-group study—Iressa in NSCLC versus vinorelbine investigation in the elderly (INVITE; D791AC00001, NCT00256711 [ClinicalTrials.gov] )—assessed the activity of gefitinib or vinorelbine in chemotherapy-naïve elderly patients who had locally advanced or metastatic NSCLC. Patients were randomly assigned in a 1:1 manner to receive either gefitinib (250 mg/d orally) or vinorelbine (30 mg/m² infusion on days 1 and 8 of a 21-day cycle). Patients who were randomly assigned to gefitinib could continue treatment until clinical or objective progression, unacceptable toxicity, or patient withdrawal. Patients with confirmed objective progression who were considered by the patient and the investigator to derive clinical benefit could continue treatment with gefitinib. Patients who were randomly assigned to vinorelbine could continue treatment for up to a maximum of six cycles or until clinical or objective progression, unacceptable toxicity, or patient withdrawal. At the point of disease progression, further therapy was selected at the discretion of the patient and investigator. Dose interruptions of gefitinib of up to 14 days were allowed. The dose of vinorelbine could be adjusted according to prescribing guidelines.

The primary end point was PFS, which was defined as the time from random assignment to the earliest occurrence of objective disease progression or death from any cause. Secondary end points were overall survival (OS; defined as the time to death), objective response rate (ORR), quality of life (QOL), pulmonary symptom improvement (PSI), and tolerability. Objective tumor response was assessed every 6 weeks until radiologic evidence of progression was noted with the Response Evaluation Criteria in Solid Tumors (RECIST) criteria.¹³ Patients who discontinued for reasons other than disease progression continued to have objective tumor assessments every 6 weeks.

QOL was assessed by using the Functional Assessment of Cancer Therapy-Lung (FACT-L) questionnaire,^14,15 which was completed pretreatment, once every 3 weeks until week 18, every 6 weeks thereafter, on discontinuation, and 3 weeks after discontinuation. FACT-L questionnaires were completed at home before clinic visits. The Trial Outcome Index (TOI) is the sum of the physical well-being, functional well-being, and Lung Cancer Subscale (LCS) scores of the FACT-L. The LCS of the FACT-L was completed as part of the FACT-L questionnaire and was completed every week until treatment discontinuation. Improvement in pulmonary symptoms was assessed from the four pulmonary items of the seven-item LCS, a validated instrument with a minimal important difference of two points.^16,17 PSI was defined as an improvement of at least two points that was maintained for at least 21 days in at least one moderate or severe pulmonary item of the LCS.

AEs were assessed at each visit (every 3 weeks) according to the National Cancer Institute Common Toxicity Criteria (NCI-CTC; version 3.0).

Exploratory end points included association of EGFR gene copy number (assessed by fluorescent in situ hybridization [FISH]⁹), EGFR protein expression (by using the DAKO EGFR pharmDx kit [DAKO, Glostrup, Denmark]), and EGFR tyrosine kinase domain mutations with gefitinib and vinorelbine activity.

Patients
Patients were eligible if they were at least 70 years of age and had histologically confirmed stage IIIB or stage IV NSCLC; at least one measurable lesion according to RECIST criteria; histological biopsy and paraffin block from the original tumor or metastatic site; no prior chemotherapy, biologic, or immunologic therapy; WHO performance status of 0, 1, or 2; and a life expectancy of at least 12 weeks. Exclusion criteria included newly diagnosed central nervous system metastases that had not yet been treated; any evidence of clinically active interstitial lung disease (ILD); other coexisting malignancies or malignancies diagnosed within the last 5 years other than basal cell carcinoma or cervical cancer in situ; prior treatment with EGFR inhibitors; and treatment with an investigational drug within 30 days.

All patients provided written, informed consent, and approval for the study was obtained from independent ethics committees. The study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and that are consistent with the International Conference on Harmonisation/Good Clinical Practice and applicable regulatory requirements and with the AstraZeneca policy on bioethics.

Statistical Analysis
The sample size was calculated with an assumption of a median PFS of 3 months in the vinorelbine group and the detection of a hazard ratio (HR) of 0.67 (gefitinib v vinorelbine). One hundred fifty-one progression events were estimated to be sufficient to detect this difference, with 80% power and an assumption of a two-sided level of 10%. Ninety-six patients per arm were estimated to be sufficient.

The statistical analyses for PFS and OS were performed by using a proportional hazards model that included the following prognostic factors: sex (male v female), WHO performance status (0 to 1 v 2), histology (adenocarcinoma v other), smoking history (ever v never), and stage (locally advanced v metastatic). The HR (gefitinib v vinorelbine) was estimated with its associated CI (90% and 95% CIs for PFS; 95% CI for OS) and P value. An HR less than 1 indicated a favorable outcome for gefitinib compared with vinorelbine. The PFS rates at 4 and 6 months were obtained from the Kaplan-Meier technique. Median, 6-month, and 1-year survivals were estimated for each treatment group. These analyses were performed on the intent-to-treat population of all randomly assigned patients. ORR was compared between geftinib and vinorelbine by using a logistic regression model and the odds ratio with its associated 95% CI. The number and percentage of patients with a best objective response of complete response, partial response, or stable disease were summarized to provide an estimate of the disease control rate. PSI and QOL improvement rates were analyzed by using a logistic regression model. The odds ratio and its associated 95% CI were estimated for the populations who were assessable for PSI (ie, patients with at least one LCS pulmonary item with a baseline score of 0 or 1 and a postbaseline assessment) and assessable for QOL (ie, patients with a baseline and a postbaseline QOL assessment), respectively.

Gefitinib v vinorelbine HRs and 95% CIs for PFS and OS were estimated for the FISH-positive and FISH-negative subgroups. Efficacy comparisons between FISH subgroups were also carried out for gefitinib and vinorelbine separately.

	RESULTS

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
From July 2004 to December 2005, 196 patients were enrolled at 41 centers in 10 countries (Fig 1). The study continued until 151 progression events had occurred; the data cutoff date was February 24, 2006. Demographic and baseline characteristics are listed in Table 1. Most patients were male (77% and 74% in the gefitinib and vinorelbine groups, respectively) and had a smoking history (82% and 89% in the gefitinib and vinorelbine groups, respectively). Overall, 35% of patients in the gefitinib group and 46% of patients in the vinorelbine group had adenocarcinoma (including bronchoalveolar carcinoma). As might be expected in a small study, there were some small imbalances between the treatment groups in terms of demographic and other patient characteristics, but these were considered unlikely to have affected the interpretation of the results (particularly as the efficacy analyses adjusted for these imbalances and other key baseline characteristics, such as sex, histology, smoking history, disease status, ethnicity, and performance status).

View larger version (39K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. Study flow.

Efficacy
The HR for PFS in the gefitinib group compared with the vinorelbine group was 1.19 (90% CI, 0.90 to 1.56; 95% CI, 0.85 to 1.65; P = .310; Fig 2). The median PFS rates were 2.7 and 2.9 months for gefitinib and vinorelbine, respectively. PFS rates at 4 and 6 months were 27.0% and 14.9% (for gefitinib) and 39.8% and 23.6% (for vinorelbine), respectively. At the time of data cutoff, the median follow-up times for PFS were 2.8 and 2.5 months for gefitinib and vinorelbine, respectively.

View larger version (14K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 2. Kaplan-Meier curves for (A) progression-free survival and (B) overall survival. HR, hazard ratio.

ORRs were 3.1% (95% CI, 0.6 to 8.8) and 5.1% (95% CI, 1.7 to 11.4), and disease control rates were 43.3% and 53.5%, for gefitinib and vinorelbine, respectively. The preplanned logistic regression analysis of ORR could not be performed because of the small number of responses.

QOL
Overall QOL improvement rates, as assessed by the total FACT-L and TOI scores, were higher with gefitinib than with vinorelbine (24.3% v 10.9%; odds ratio, 2.97; 95% CI, 1.06 to 8.34 for FACT-L analyses and 22.9% v 6.3%; odds ratio, 5.47; 95% CI, 1.61 to 18.56 for TOI analyses). The overall disease-related LCS improvement rates and PSI rates were similar with gefitinib and vinorelbine (42.9% v 39.1%; odds ratio, 1.19; 95% CI, 0.57 to 2.48 for LCS analyses and 36.6% v 31.0%; odds ratio, 1.20; 95% CI, 0.43 to 3.33 for PSI analyses).

Biomarker Analyses
Of the 196 patients who underwent random assignment, 191 patients provided a tumor sample. The following numbers of samples were assessable as positive or negative: 158 for EGFR gene copy number (by FISH), 157 for EGFR protein expression, and 65 for EGFR mutation. Mutation analysis was performed in a limited number of instances, because ethics committee approval was obtained in only a few centers. In the small subgroup of EGFR FISH-positive patients (54 [34%] of 158 patients with known FISH status), those treated with vinorelbine achieved better PFS and OS outcomes than patients treated with gefitinib: HRs (gefitinib v vinorelbine) were 3.13 (95% CI, 1.45 to 6.76) and 2.88 (95% CI, 1.21 to 6.83), respectively (Fig 3). Furthermore, patients who were FISH-positive and who were treated with gefitinib had a nonsignificant trend toward poorer PFS and OS outcomes than patients who were FISH-negative and who were treated with gefitinib: HRs for FISH-positive versus FISH-negative patients who were treated with gefitinib were 1.31 (95% CI, 0.77 to 2.22) for PFS and 1.61 (95% CI, 0.87 to 3.01) for OS. Conversely, patients who were FISH-positive and who were treated with vinorelbine had a nonsignificant trend toward improved PFS and OS outcomes than patients who were FISH-negative and who were treated with vinorelbine. HRs for FISH-positive versus FISH-negative patients who were treated with vinorelbine were 0.77 (95% CI, 0.43 to 1.39) for PFS and 0.52 (95% CI, 0.25 to 1.10) for OS. Of the patients with assessable tumor samples, the low numbers of patients with EGFR protein expression–negative (13 [8.3%] of 157) or EGFR mutation–positive (7 [10.8%] of 65) tumors meant that evaluations of clinical efficacy according to EGFR protein expression or mutation status would not be meaningful.

View larger version (26K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 3. Kaplan-Meier curves for progression-free survival in (A) epidermal growth factor receptor (EGFR) fluorescent in situ hybridization (FISH) –positive and (B) EGFR FISH-negative patients, and overall survival in (C) EGFR FISH-positive and (D) EGFR FISH-negative patients by FISH status (exploratory analyses). HR, hazard ratio.

	DISCUSSION

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
Treatment of elderly patients who have NSCLC remains a challenge. Standard chemotherapy produces modest results and requires intravenous administration, which highlights the urgent need for more effective therapies. This study, the first randomized EGFR-TKI study conducted in untreated elderly patients who have advanced NSCLC, showed no statistical difference between gefitinib and vinorelbine in terms of PFS, OS, and response rate; the toxicity profile and overall QOL assessments favored gefitinib. For patients with advanced disease, QOL and symptom relief represent important clinical end points, because a definitive cure is not achievable. Although the LCS was similar in both arms, drug-related AEs were less frequent in the gefitinib arm. Patients treated with gefitinib had a numerically lower incidence of fatigue as an AE and of gastrointestinal AEs, notably constipation, which is an important side effect in the elderly population that requires particular efforts to avoid or at least minimize. Moreover, hematologic toxicity was confined to patients treated with vinorelbine. Many patients who received vinorelbine experienced deterioration in hematologic parameters, whereas the majority of patients who received gefitinib experienced no changes from baseline in NCI-CTC grade for hematologic parameters (data not shown). Although oral vinorelbine is also available, these findings suggest that the oral EGFR-TKI gefitinib could represent a more tolerable alternative to vinorelbine in the elderly population; phase III studies are now required to additionally explore this potential. This study included a large percentage of patients with good performance status. This aspect could represent a potential limitation for the clinical implication of the study, because elderly fit patients could be safely treated with standard platinum-based doublets.

A previous study evaluated the role of the TKI erlotinib in elderly patients with NSCLC.¹⁸ In this previous study, erlotinib produced a 10% response rate, a 3.5-month time to progression, and a 10.9-month median survival.¹⁸ These encouraging results were observed in a cohort of patients with favorable characteristics, as shown by the high percentage of females (50%) and adenocarcinomas (60%) and by the low percentage of individuals with performance status 2 (only 10%). The present study probably better reflects a European population seen in clinical practice, because the vast majority of patients were male (77%), were smokers (82%), and had squamous cell carcinoma (48%). These clinical characteristics could also explain the low percentage of observed responders, because female sex and adenocarcinoma histology are well-known clinical predictors for response to TKIs.^7,8,19

When this study was designed, patient tumor sample collection and biomarker analyses were planned, although no predictor of TKI sensitivity was known. Most patients were analyzed for EGFR gene copy number by FISH; surprisingly, those who were EGFR FISH-positive and who received gefitinib appeared to have poorer outcomes than those who were EGFR FISH-negative and who received gefitinib. This finding was unexpected and was in contrast to previous observations, which showed a survival improvement for patients who were EGFR FISH-positive and who received an EGFR-TKI.^9,12,20 A number of hypotheses to explain the EGFR FISH results have been explored, including the effects of differences in performance status and mean age between the two arms, compromised gefitinib exposure, and the treatment-naïve status of patients included in this study (whereas those included in previous studies had received prior lines of therapy). However, a clear explanation for the discrepancy in FISH results is not currently evident. Because of the reported association of EGFR FISH-positive status with the presence of EGFR mutations,⁹ and because K-Ras mutations represent an important event associated with intrinsic resistance to EGFR-TKIs,²¹ it could be useful to perform EGFR as well as K-Ras mutation analyses in this patient population. Unfortunately, the majority of ethics committees in centers that participated in the study did not approve gene mutation analyses as complementary tests for this study. Therefore, we were unable to assess the impact of EGFR gene mutations on study therapies. There were too few patients in the K-Ras mutation analysis to draw any accurate conclusions. Another hypothesis, as suggested by recent results from the study, Iressa non–small-cell lung cancer trial evaluating response and survival against taxotere,²² is that EGFR biomarkers and K-Ras mutation status are predictive factors for sensitivity to both EGFR-TKIs and chemotherapy.

In conclusion, there was no statistical difference between gefitinib and vinorelbine for efficacy, and gefitinib appeared to have an improved toxicity profile compared with vinorelbine in unselected elderly patients who had advanced NSCLC. Results obtained in patients who were EGFR FISH-positive were unexpected and in contrast with previous observations, which highlights the urgent need for prospective biomarker studies.

	AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Employment or Leadership Position: Serban Ghiorghiu, AstraZeneca (C); Emma L. Duffield, AstraZeneca (C); Alison A. Armour, AstraZeneca (C); Georgina Speake, AstraZeneca (C) Consultant or Advisory Role: Lucio Crinò, AstraZeneca (U); Martin Reck, Roche (U), Boehringer-Ingelheim (U); Fred R. Hirsch, AstraZeneca (U), Roche (U), Eli Lilly & Co (U) Stock Ownership: Serban Ghiorghiu, AstraZeneca; Emma L. Duffield, AstraZeneca; Alison A. Armour, AstraZeneca; Georgina Speake, AstraZeneca Honoraria: Lucio Crinò, AstraZeneca; Martin Reck, Boehringer-Ingelheim, Roche, Eli Lilly & Co, Bayer; Michael Cullen, AstraZeneca Research Funding: Fred R. Hirsch, AstraZeneca, OSI Pharmaceuticals, Merck & Co; Marileila Varella-Garcia, AstraZeneca; Michael Cullen, AstraZeneca Expert Testimony: None Other Remuneration: None

	AUTHOR CONTRIBUTIONS

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
Conception and design: Lucio Crinò, Serban Ghiorghiu, Emma L. Duffield, Michael Cullen

Provision of study materials or patients: Lucio Crinò, Federico Cappuzzo, Petr Zatloukal, Martin Reck, Milos Pesek, Joyce C. Thompson, Hugo E.R. Ford, Michael Cullen

Collection and assembly of data: Federico Cappuzzo, Petr Zatloukal, Martin Reck, Joyce C. Thompson, Fred R. Hirsch, Serban Ghiorghiu, Emma L. Duffield, Alison A. Armour, Michael Cullen

Data analysis and interpretation: Lucio Crinò, Federico Cappuzzo, Martin Reck, Fred R. Hirsch, Marileila Varella-Garcia, Serban Ghiorghiu, Emma L. Duffield, Alison A. Armour, Georgina Speake, Michael Cullen

Manuscript writing: Lucio Crinò, Federico Cappuzzo, Fred R. Hirsch, Serban Ghiorghiu, Emma L. Duffield, Alison A. Armour, Michael Cullen

Final approval of manuscript: Lucio Crinò, Federico Cappuzzo, Petr Zatloukal, Martin Reck, Milos Pesek, Joyce C. Thompson, Hugo E.R. Ford, Fred R. Hirsch, Marileila Varella-Garcia, Serban Ghiorghiu, Emma L. Duffield, Alison A. Armour, Georgina Speake, Michael Cullen

	Appendix

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
Biomarker Assessments
A tumor tissue sample from the diagnostic block was analyzed for epidermal growth factor receptor (EGFR) gene copy number by using FISH according to a previously described protocol (Cappuzzo F, Hirsch FR, Rossi E, et al: J Natl Cancer Inst 97:643-655, 2005). Patients were considered to have a high EGFR gene copy number (FISH-positive) if there was high polysomy (ie, 4 copies in > 40% of cells) or gene amplification (ie, presence of tight gene clusters, a gene-to-chromosome ratio per cell of 2, or 15 copies of EGFR per cell in 10% of cells analyzed). EGFR protein expression status was assessed by using the DAKO EGFR pharmDx kit (DAKO, Glostrup, Denmark). Patients were classified as EGFR-positive (ie, 10% cells stained) or EGFR-negative (ie, < 10% cells stained). EGFR gene mutations were investigated by the amplification refractory mutation system (for exon 19 deletions and L858R mutations) and by gene sequencing (for mutations in exons 18 to 21). Three independent polymerase chain reactions were performed for sequencing; mutations had to be detected in at least two traces, each originating from independent polymerase chain reactions.

	ACKNOWLEDGMENTS

 
We thank the investigators and patients who participated in the study and Margaret Skokan, BS, Sujatha Gajapathy, MS and Yun Xiao, PhD, of the University of Colorado Cancer Center Cytogenetics Core for their assistance with the fluorescent in situ hybridization (FISH) analyses. We also thank Annette Smith, PhD, from Complete Medical Communications, who provided editing assistance that was funded by AstraZeneca.

	NOTES

 
Supported by AstraZeneca, Macclesfield, Cheshire, United Kingdom.

Presented in part at the 5th International Symposium on Targeted Anticancer Therapies, March 8-10, 2007, Amsterdam, the Netherlands, and at the 12th World Conference on Lung Cancer, September 2-6, 2007, Seoul, Korea.

Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.

Clinical trial information can be found for the following: NCT00256711 [ClinicalTrials.gov] .

	REFERENCES

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
1. Bunn PA, Lilenbaum R: Chemotherapy for elderly patients with advanced non–small-cell lung cancer. J Natl Cancer Inst 95:341-343, 2003[Free Full Text]

2. Gridelli C: Does chemotherapy have a role as palliative therapy for unfit or elderly patients with non–small-cell lung cancer? Lung Cancer 38:S45-S50, 2002[CrossRef][Medline]

3. Spiro SG, Silvestri GA: The treatment of advanced non–small-cell lung cancer. Curr Opin Pulm Med 11:287-291, 2005[CrossRef][Medline]

4. Langer CJ, Manola J, Bernardo P, et al: Cisplatin-based therapy for elderly patients with advanced non–small-cell lung cancer: Implications of Eastern Cooperative Oncology Group 5592, a randomized trial. J Natl Cancer Inst 94:173-181, 2002[Abstract/Free Full Text]

5. Gridelli C, Perrone F, Gallo C, et al: Chemotherapy for elderly patients with advanced non–small-cell lung cancer: The Multicenter Italian Lung Cancer in the Elderly Study (MILES) phase III randomized trial. J Natl Cancer Inst 95:362-372, 2003[Abstract/Free Full Text]

6. Le Chevalier T, Brisgand D, Douillard J-Y, et al: Randomized study of vinorelbine and cisplatin versus vindesine and cisplatin versus vinorelbine alone in advanced non–small-cell lung cancer: Results of a European multicenter trial including 612 patients. J Clin Oncol 12:360-367, 1994[Abstract]

7. Fukuoka M, Yano S, Giaccone G, et al: Multi-institutional randomized phase II trial of gefitinib for previously treated patients with advanced non–small-cell lung cancer. J Clin Oncol 21:2237-2246, 2003[Abstract/Free Full Text]

8. Kris MG, Natale RB, Herbst RS, et al: Efficacy of gefitinib, an inhibitor of the epidermal growth factor receptor tyrosine kinase, in symptomatic patients with non–small cell lung cancer: A randomized trial. JAMA 290:2149-2158, 2003[Abstract/Free Full Text]

9. Cappuzzo F, Hirsch FR, Rossi E, et al: Epidermal growth factor receptor gene and protein and gefitinib sensitivity in non–small-cell lung cancer. J Natl Cancer Inst 97:643-655, 2005[Abstract/Free Full Text]

10. Lynch TJ, Bell DW, Sordella R, et al: Activating mutations in the epidermal growth factor receptor underlying responsiveness of non–small-cell lung cancer to gefitinib. N Engl J Med 350:2129-2139, 2004[Abstract/Free Full Text]

11. Paez JG, Jänne PA, Lee JC, et al: EGFR mutations in lung cancer: Correlation with clinical response to gefitinib therapy. Science 304:1497-1500, 2004[Abstract/Free Full Text]

12. Tsao M-S, Sakurada A, Cutz J-C, et al: Erlotinib in lung cancer: Molecular and clinical predictors of outcome. N Engl J Med 353:133-144, 2005[Abstract/Free Full Text]

13. Therasse P, Arbuck SG, Eisenhauer EA, et al: New guidelines to evaluate the response to treatment in solid tumors. J Natl Cancer Inst 92:205-216, 2000[Abstract/Free Full Text]

14. Cella DF, Tulsky DS, Gray G, et al: The functional assessment of cancer therapy scale: Development and validation of the general measure. J Clin Oncol 11:570-579, 1993[Abstract/Free Full Text]

15. Cella DF, Bonomi AE, Lloyd SR, et al: Reliability and validity of the Functional Assessment of Cancer Therapy-Lung (FACT-L) quality of life instrument. Lung Cancer 12:199-220, 1995[CrossRef][Medline]

16. Cella D, Eton DT, Fairclough DL, et al: What is a clinically meaningful change on the Functional Assessment of Cancer Therapy-Lung (FACT-L) Questionnaire? Results from Eastern Cooperative Oncology Group (ECOG) Study 5592. J Clin Epidemiol 55:285-295, 2002[CrossRef][Medline]

17. Cella DF, Herbst RS, Lynch TJ, et al: Clinically meaningful improvement in symptoms and quality of life for patients with non–small-cell lung cancer receiving gefitinib in a randomized controlled trial. J Clin Oncol 23:2946-2954, 2005[Abstract/Free Full Text]

18. Jackman DM, Yeap BY, Lindeman NI, et al: Phase II clinical trial of chemotherapy-naive patients 70 years of age treated with erlotinib for advanced non–small-cell lung cancer. J Clin Oncol 25:760-766, 2007[Abstract/Free Full Text]

19. Thatcher N, Chang A, Parikh P, et al: Gefitinib plus best supportive care in previously treated patients with refractory advanced non–small-cell lung cancer: Results from a randomised, placebo-controlled, multicentre study (Iressa Survival Evaluation in Lung Cancer). Lancet 366:1527-1537, 2005[CrossRef][Medline]

20. Hirsch FR, Varella-Garcia M, Bunn PA Jr, et al: Molecular predictors of outcome with gefitinib in a Phase III placebo-controlled study in advanced non–small-cell lung cancer. J Clin Oncol 24:5034-5042, 2006[Abstract/Free Full Text]

21. Pao W, Wang TY, Riely GJ, et al: KRAS mutations and primary resistance of lung adenocarcinomas to gefitinib or erlotinib. PLoS Med 2(1):e17, 2005[CrossRef][Medline]

22. Douillard JY, Kim ES, Hirsh V, et al: Gefitinib (IRESSA) versus docetaxel in patients with locally advanced or metastatic non–small-cell lung cancer pre-treated with platinum-based chemotherapy: A randomized, open-label Phase III study (INTEREST). Presented at the 12th World Conference on Lung Cancer, Seoul, Korea, September 26, 2007

Submitted October 25, 2007; accepted February 28, 2008.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Facebook    Reddit    Technorati    Twitter    What's this?

This article has been cited by other articles:

				M Varella-Garcia, J Diebold, D A Eberhard, K Geenen, A Hirschmann, M Kockx, I Nagelmeier, J Ruschoff, M Schmitt, S Arbogast, et al. EGFR fluorescence in situ hybridisation assay: guidelines for application to non-small-cell lung cancer J. Clin. Pathol., November 1, 2009; 62(11): 970 - 977. [Abstract] [Full Text] [PDF]

				A. G. Pallis, C. Gridelli, J. P. van Meerbeeck, L. Greillier, U. Wedding, D. Lacombe, J. Welch, C. P. Belani, and M. Aapro EORTC Elderly Task Force and Lung Cancer Group and International Society for Geriatric Oncology (SIOG) experts' opinion for the treatment of non-small-cell lung cancer in an elderly population Ann. Onc., August 28, 2009; (2009) mdp360v1. [Abstract] [Full Text] [PDF]

				M. C. GARASSINO, K. BORGONOVO, A. ROSSI, A. MANCUSO, O. MARTELLI, A. TINAZZI, S. DI COSIMO, N. LA VERDE, P. SBURLATI, C. BIANCHI, et al. Biological and Clinical Features in Predicting Efficacy of Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors: A Systematic Review and Meta-analysis Anticancer Res, July 1, 2009; 29(7): 2691 - 2701. [Abstract] [Full Text] [PDF]

				C. Gridelli, P. Maione, and A. Rossi Chemotherapy and Targeted Therapy for Older Patients with Advanced Non-small Cell Lung Cancer ASCO Educational Book, January 1, 2009; 2009(1): 283 - 287. [Abstract] [Full Text] [PDF]

				M. A. Socinski What Guides Decisions about the Use of Epidermal Growth Factor Receptor Antibody or Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in Advanced Non-small Cell Lung Cancer? ASCO Educational Book, January 1, 2009; 2009(1): 436 - 443. [Abstract] [Full Text] [PDF]

				R. C. Kane The Clinical Significance of Statistical Significance Oncologist, November 1, 2008; 13(11): 1129 - 1133. [Abstract] [Full Text] [PDF]

				S. E. Dahlberg, R. J. Gray, and B. E. Johnson Gefitinib for Recurrent Non-Small-Cell Lung Cancer: All Things Are Not Created Equal J. Clin. Oncol., September 10, 2008; 26(26): 4233 - 4235. [Full Text] [PDF]

This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Crinò, L. Articles by Cullen, M. Search for Related Content PubMed PubMed Citation Articles by Crinò, L. Articles by Cullen, M. Social Bookmarking                            What's this?