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ORIGINAL REPORTS
June 13, 2011

Biomarker Analyses and Final Overall Survival Results From a Phase III, Randomized, Open-Label, First-Line Study of Gefitinib Versus Carboplatin/Paclitaxel in Clinically Selected Patients With Advanced Non–Small-Cell Lung Cancer in Asia (IPASS)

Publication: Journal of Clinical Oncology

Abstract

Purpose

The results of the Iressa Pan-Asia Study (IPASS), which compared gefitinib and carboplatin/paclitaxel in previously untreated never-smokers and light ex-smokers with advanced pulmonary adenocarcinoma were published previously. This report presents overall survival (OS) and efficacy according to epidermal growth factor receptor (EGFR) biomarker status.

Patients and Methods

In all, 1,217 patients were randomly assigned. Biomarkers analyzed were EGFR mutation (amplification mutation refractory system; 437 patients evaluable), EGFR gene copy number (fluorescent in situ hybridization; 406 patients evaluable), and EGFR protein expression (immunohistochemistry; 365 patients evaluable). OS analysis was performed at 78% maturity. A Cox proportional hazards model was used to assess biomarker status by randomly assigned treatment interactions for progression-free survival (PFS) and OS.

Results

OS (954 deaths) was similar for gefitinib and carboplatin/paclitaxel with no significant difference between treatments overall (hazard ratio [HR], 0.90; 95% CI, 0.79 to 1.02; P = .109) or in EGFR mutation–positive (HR, 1.00; 95% CI, 0.76 to 1.33; P = .990) or EGFR mutation–negative (HR, 1.18; 95% CI, 0.86 to 1.63; P = .309; treatment by EGFR mutation interaction P = .480) subgroups. A high proportion (64.3%) of EGFR mutation–positive patients randomly assigned to carboplatin/paclitaxel received subsequent EGFR tyrosine kinase inhibitors. PFS was significantly longer with gefitinib for patients whose tumors had both high EGFR gene copy number and EGFR mutation (HR, 0.48; 95% CI, 0.34 to 0.67) but significantly shorter when high EGFR gene copy number was not accompanied by EGFR mutation (HR, 3.85; 95% CI, 2.09 to 7.09).

Conclusion

EGFR mutations are the strongest predictive biomarker for PFS and tumor response to first-line gefitinib versus carboplatin/paclitaxel. The predictive value of EGFR gene copy number was driven by coexisting EGFR mutation (post hoc analysis). Treatment-related differences observed for PFS in the EGFR mutation–positive subgroup were not apparent for OS. OS results were likely confounded by the high proportion of patients crossing over to the alternative treatment.

Introduction

The epidermal growth factor receptor (EGFR) represents an important signaling pathway that regulates tumorigenesis and cell survival and is frequently overexpressed in the development and progression of non–small-cell lung cancer (NSCLC).14 EGFR tyrosine kinase inhibitors (TKIs) such as gefitinib (Iressa, AstraZeneca, Macclesfield, United Kingdom) are effective in the treatment of relapsed NSCLC,5,6 with certain clinical subgroups deriving greater clinical benefit (adenocarcinoma histology, Asian ethnicity, female sex, and never-smoker status).57 These subgroups are associated with a higher incidence of activating somatic mutations of the EGFR gene.810 Optimization of anti-EGFR therapy depends on patient selection, and the exploration and identification of predictive biomarkers is important.
EGFR mutations, EGFR gene copy number, and EGFR protein expression are three EGFR-related biomarkers that have been studied in major clinical trials.1114 The significant overlap between EGFR biomarkers and limited availability of tumor samples in some studies made the interpretation of their individual predictive and prognostic values difficult.
Prolonged progression-free survival (PFS) and higher objective response rate (ORR) have been reported in patients with high EGFR gene copy number in single-arm and placebo-controlled randomized studies.12,1517 However, in the large phase III, randomized Iressa NSCLC Trial Evaluating Response and Survival Versus Taxotere (INTEREST) study with an active comparator, high EGFR gene copy number was not predictive for differential survival between gefitinib and docetaxel in patients with advanced NSCLC.18
The Iressa Pan-Asia Study (IPASS) is a phase III, randomized study of gefitinib versus carboplatin/paclitaxel in previously untreated never-smokers and light ex-smokers with advanced pulmonary adenocarcinoma in East Asia. As previously reported, IPASS exceeded its primary objective of noninferiority, demonstrating superiority of gefitinib relative to carboplatin/paclitaxel for PFS in this clinically selected population.19 The treatment effect was not constant over time, driven by different outcomes according to mutation status. In the subgroup of patients with EGFR mutation–positive tumors, PFS was significantly longer for gefitinib versus carboplatin/paclitaxel (hazard ratio [HR], 0.48; 95% CI, 0.36 to 0.64; P < .001; median PFS, 9.5 v 6.3 months). Conversely, carboplatin/paclitaxel was superior in the EGFR mutation–negative subgroup (HR, 2.85; 95% CI, 2.05 to 3.98; P < .001; median PFS, 5.5 v 1.5 months); similarly, ORR significantly favored gefitinib and carboplatin/paclitaxel in the EGFR mutation–positive and EGFR mutation–negative subgroups, respectively.19 A total of 1,038 of 1,217 patients consented to the preplanned exploratory biomarker analyses; 683 patients provided samples.
Early analysis of survival data (37% maturity) was presented in 2008.19 Here we present the final results of the survival analyses and the results of the preplanned and post hoc analyses of the relationships between EGFR biomarkers (EGFR mutation, EGFR gene copy number, and EGFR protein expression) and clinical outcomes from IPASS.

Patients and Methods

Study Design and Treatment

Full details of IPASS have been published previously.19 Eligible patients had stage IIIB to IV pulmonary adenocarcinoma (including bronchoalveolar carcinoma), were either never-smokers (< 100 cigarettes in their lifetime) or light ex-smokers (stopped smoking ≥ 15 years previously and smoked ≤ 10 pack-years), and had received no prior chemotherapy or biologic or immunologic therapy.
Patients were randomly assigned 1:1 to gefitinib (250 mg/d) or carboplatin/paclitaxel (Paraplatin/Taxol, Bristol-Myers Squibb, Princeton, NJ; paclitaxel 200 mg/m2 was given intravenously over 3 hours on day 1, immediately followed by carboplatin area under the serum concentration-time curve [AUC] 5.0 or 6.0 intravenously over 15 to 60 minutes in once every 3 weeks cycles for ≤ six cycles).
The primary objective of IPASS was noninferiority of gefitinib relative to carboplatin/paclitaxel in terms of PFS. ORR and overall survival (OS) were secondary end points. Evaluation of biomarker status (EGFR mutation, gene copy number, and protein expression) and efficacy of gefitinib versus carboplatin/paclitaxel were preplanned exploratory objectives. Post hoc analyses included clinical outcomes according to EGFR mutation subtype, EGFR gene copy number by EGFR mutation status, and clinical outcomes for patients with tumor EGFR gene high polysomy, and EGFR gene amplification. Correlation between EGFR mutation status and EGFR gene copy number was also investigated.
Patients provided written, informed consent with separate consent obtained for optional provision of tumor material for biomarker analyses. Study approval was obtained from independent ethics committees at each institution. The study was conducted in accordance with the Declaration of Helsinki, the International Conference on Harmonization/Good Clinical Practice, applicable regulatory requirements, and AstraZeneca's policy on bioethics.

Biomarker Analyses

Biomarker status was determined by analyzing paraffin-embedded archival tumor tissue in the following priority order: (1) EGFR mutation status, (2) EGFR gene copy number, (3) EGFR protein expression. Analyses were conducted at two central laboratories (Genzyme, Framingham, MA, and Quintiles-Lab in association with Peking Union Medical College Hospital, Beijing, China); scientists were blinded to clinical outcome and randomly assigned treatment. Samples underwent central histopathologic review; only those considered suitable for downstream biomarker analysis were progressed (on the basis of quality, sample source, and tumor content). If a patient provided more than one sample, the appropriate section was selected before database lock and analyzed on the basis of sample quality and largest area of tumor tissue.20
EGFR mutations were detected by using an amplification mutation refractory system with an EGFR mutation detection kit (DxS, Manchester, United Kingdom).21,22 Patients were considered EGFR mutation positive if at least one of 29 EGFR mutations (Data Supplement) was detected. Additional validation for samples with T790M mutations was performed by using three methods: DNA sequencing, multithreaded electronic polymerase chain reaction sequencing, and an alternative amplification mutation refractory system assay (Data Supplement). EGFR gene copy number was measured by using fluorescent in situ hybridization and a previously published methodology.15 High EGFR gene copy number was defined according to the University of Colorado Scoring System, which included both high polysomy (≥ four copies in ≥ 40% of cells; score 5) or gene amplification (presence of tight EGFR gene clusters and a ratio of gene/chromosome per cell ≥ two, or ≥ 15 copies of EGFR per cell in ≥ 10% of analyzed cells; score 6).15 EGFR protein expression was assessed by immunohistochemistry by using the DAKO EGFR pharmDx kit (Dako, Glostrup, Denmark). Positive EGFR protein expression status was defined as having ≥ 10% of cells stained.

Statistical Analyses

The study statistician performed the statistical analyses at AstraZeneca. In the overall population and clinical subgroups, OS was analyzed by using a Cox proportional hazards model adjusted for the same covariates as for the primary PFS analysis (WHO performance status, 0 to 1 v 2; smoking history, never-smoker v light ex-smoker; and sex, female v male). The HR (gefitinib:carboplatin/paclitaxel) was estimated with 95% CIs and P values. Final analysis of OS was planned for when 944 deaths (78%) had occurred in the intent-to-treat (ITT) population, the same level of maturity as for PFS.
For each biomarker, patients were classified as positive, negative, or unknown. For each of these groups, HRs, 95% CIs, and P values were estimated for PFS and OS (by using a Cox proportional hazards model adjusted for the same covariates as for the primary PFS analysis in the ITT population). The biomarker status by randomly assigned treatment interaction was assessed individually for each biomarker for PFS and OS by using a Cox proportional hazards model adjusted for randomly assigned treatment, biomarker status (positive or negative), and the biomarker status by treatment interaction by using a 10% significance level to indicate potential predictive factors for gefitinib versus carboplatin/paclitaxel. When there were fewer than 20 events in a subgroup for PFS or OS, only descriptive summaries were produced. Odds ratios, 95% CIs, and P values were estimated for ORRs by using a logistic regression model adjusted for the same covariates as those used in the analysis of PFS in the ITT population.

Results

Patients

Patient disposition is presented in Figure 1. Therapies received postdiscontinuation of randomly assigned treatment are listed in Table 1. Specifically, 83 (64.3%) of 129 patients with EGFR mutation–positive tumors randomly assigned to carboplatin/paclitaxel received subsequent EGFR TKIs.
Fig 1. CONSORT diagram. (*) Among the 112 patients who failed screening, the main reasons for exclusion were abnormal serum creatinine (> 1.5 × upper limit of reference range)/creatinine clearance (≤ 60 mL/min) levels; untreated CNS metastases; or low neutrophil (< 2.0 × 109/L), platelet (< 100 × 109/L), or hemoglobin (< 10 g/dL) counts. (†) Cutoff dates: June 14, 2010, for overall survival (OS) and April 14, 2008, for progression-free survival (PFS). (‡) All patients who were randomly assigned to a study group were included in the intent-to-treat (ITT) analysis. (§) Patients who did not deviate substantially from the inclusion and exclusion criteria at entry or from the protocol were included in the per-protocol analysis. (∥) All patients who received at least one dose of study treatment were included in the safety analysis. (¶) All patients with a baseline and at least one postbaseline quality-of-life assessment that could be evaluated were included in the quality-of-life analysis. (#) All patients in the ITT population with an evaluable tumor sample. Of 683 patients (56%) who provided samples, 118 were cytology samples, and 128 were histologic samples of insufficient quality and were therefore not included in the main analysis. DCO, data cutoff; EGFR, epidermal growth factor receptor.
Table 1. Summary of All Systemic Treatment After Discontinuation of Randomly Assigned Treatment in the Overall Population and in EGFR Mutation Subgroups (ITT population; data from OS data cutoff)
TreatmentOverall PopulationEGFR Mutation PositiveEGFR Mutation NegativeEGFR Mutation Unknown
G (n = 609)C/P (n = 608)G (n = 132)C/P (n = 129)G (n = 91)C/P (n = 85)G (n = 386)C/P (n = 394)
No.%No.%No.%No.%No.%No.%No.%No.%
Still on study treatment203.30032.30011.100164.100
None19031.223037.82922.03728.72123.12529.414036.316842.6
Chemotherapy39364.525141.39975.06147.36975.84451.822558.314637.1
    Platinum-based36359.6559.09068.21310.16571.41011.820853.9328.1
    C/P30149.430.57254.5005257.10017745.930.8
EGFR TKI11919.531351.53425.88364.31314.34350.67218.718747.5
    Gefitinib*§294.825041.164.56147.344.43338.8194.915639.6
    Erlotinib§7111.78313.71612.13124.099.978.24611.94511.4
    Other EGFR TKI§335.4355.81511.4129.322.255.9164.1184.6
NOTE. A patient may appear in more than one post-discontinuation treatment group. Patients may have received the same first- and second-line therapy. “None” is defined as patients who did not receive any form of cancer treatment after discontinuation of randomly assigned treatment. Radiotherapy, surgery, medical procedures, and other treatments were excluded.
Abbreviations: EGFR, epidermal growth factor receptor; ITT, intent-to-treat; OS, overall survival; G, gefitinib; C/P, carboplatin/paclitaxel; TKI, tyrosine kinase inhibitor.
*
Non–study medication after discontinuation of randomly assigned study treatment.
Patients may have also received other chemotherapy and/or EGFR TKIs during the study.
Excludes single platinum-based chemotherapy.
§
Patients may have had more than one type of EGFR TKI and are counted once for each type received.

OS (ITT Population)

The median duration of follow-up for OS was 17.0 months. At the time of data cutoff for OS (June 14, 2010), 954 patients (78%) had died (Fig 2A). In the overall population, OS was similar for gefitinib and carboplatin/paclitaxel with no significant difference between treatments (484 and 470 events, respectively; HR, 0.90; 95% CI, 0.79 to 1.02; P = .109; median OS for gefitinib, 18.8 months v 17.4 months for carboplatin/paclitaxel; Fig 2A). A consistent treatment effect was seen across all clinical subgroups (Fig 3C).
Fig 2. Kaplan-Meier curves for overall survival (OS) in the overall population and by epidermal growth factor receptor (EGFR) mutation status (intent-to-treat population). Hazard ratio (HR) < 1 implies a lower risk of death for patients treated with gefitinib. Cox analysis with covariates (performance status [0-1, 2], smoking history [never, light ex-smoker], and sex). (A) Overall population. (B) Patients with EGFR mutation–positive tumors. (C) Patients with EGFR mutation–negative tumors. (D) Patients with EGFR mutation status unknown tumors.
Fig 3. Forest plot of progression-free survival (PFS) and overall survival (OS) by epidermal growth factor receptor (EGFR) mutation status, gene copy number, and protein expression status (intent-to-treat population). (A) PFS by biomarker status. (B) OS by biomarker status. (C) OS by clinical subgroup. Hazard ratio < 1 implies a lower risk of progression or death for patients treated with gefitinib. The size of the point estimate reflects the number of events in the subgroup, with a larger circle indicating more events. Cox analysis with covariates (performance status [PS], 0 to 1 or 2; smoking history, never-smoker, light ex-smoker; and sex). OS by biomarker status; no formal adjustment for multiple testing was made, therefore, statistical significance at the traditional 5% level (95% CI < 1) cannot be claimed. Protocoled interaction tests were calculated only for OS and clinical subgroups if there was a significant interaction test for PFS. NC, not calculated.

Biomarker Evaluations

Of 683 randomly assigned patients (56.1%) who provided samples for biomarker analysis, 118 were cytology samples, which were not included in the main analysis. The number of patients with an evaluable status was 437 (35.9%) for EGFR mutation, 406 (33.4%) for EGFR gene copy number, and 365 (30.0%) for EGFR protein expression (Fig 1); the percentage of patients with a positive EGFR biomarker status was 59.7% (261 of 437), 61.3% (249 of 406), and 72.9% (266 of 365), respectively. A summary of EGFR biomarker status is presented in the Data Supplement.
The demographics, baseline characteristics, and efficacy results of patients with evaluable samples for assessment of EGFR mutation status, gene copy number, and protein expression were generally comparable with the ITT population (Table 2). There was a high degree of overlap between patients who were positive for all three biomarkers; 190 patients (78.5%) with high EGFR gene copy number also harbored an EGFR mutation; 132 patients were positive for all three biomarkers.
Table 2. Demographics, Baseline Characteristics, and Analysis Outcomes for Patients with Evaluable Tissue Samples for Each Biomarker Compared With the ITT Population
VariableEvaluable for EGFR Mutation Status* (n = 437)Evaluable for EGFR Gene Copy Number Status* (n = 406)Evaluable for EGFR Protein Expression Status* (n = 365)ITT Population (n = 1,217)
No.%HROR95% CINo.%HROR95% CINo.%HROR95% CINo.%HROR95% CI
Demographic characteristic                    
    Female33576.7   31377.1   28578.1   96579.3   
    Age < 65 years32674.6   30374.6   26271.8   89973.9   
    WHO PS 0 or 140292.0   37592.4   33491.5   1,09189.6   
    Never-smoker40592.7   37592.4   33491.5   1,14093.7   
    Locally advanced8319.0   7719.0   6718.4   29524.2   
Efficacy                    
    PFS  0.85 0.69 to 1.06  0.83 0.66 to 1.03  0.79 0.62 to 0.99  0.74 0.65 to 0.85
    ORR   1.210.83 to 1.78   1.310.88 to 1.95   1.430.94 to 2.18   1.591.25 to 2.01
    OS  1.05 0.85 to 1.29  1.10 0.89 to 1.37  1.04 0.82 to 1.30  0.90 0.79 to 1.02
NOTE. Hazard ratio (HR) < 1 implies a lower risk of progression or death on gefitinib; odds ratio (OR) > 1 implies a greater chance of response on gefitinib.
Abbreviations: ITT, intent to treat; EGFR, epidermal growth factor receptor; PS, performance status; PFS, progression-free survival; ORR, objective response rate; OS, overall survival.
*
Irrespective of whether positive or negative for each biomarker.

EGFR Mutation Status

Demographic and baseline characteristics by EGFR mutation status are shown in the Data Supplement. PFS results by EGFR mutation status have been previously published19 (Fig 3A).
There was no differential treatment effect for OS by EGFR mutation (treatment by EGFR mutation interaction test P = .480). There was no significant difference in OS for gefitinib versus carboplatin/paclitaxel in the subgroups of patients with EGFR mutation–positive tumors (104 and 95 events, respectively; HR, 1.00; 95% CI, 0.76 to 1.33; P = .990; median OS, 21.6 v 21.9 months); EGFR mutation–negative tumors (82 and 74 events, respectively; HR, 1.18; 95% CI, 0.86 to 1.63; P = .309; median OS, 11.2 v 12.7 months), or mutation status unknown tumors (298 and 301 events, respectively; HR, 0.82; 95% CI, 0.70 to 0.96; P = .015; Figs 2B, 2C, 2D, and 3B). Postdiscontinuation treatments by EGFR mutation status are listed in Table 1.

EGFR Gene Copy Number

EGFR gene copy number was a predictive biomarker for the effect of gefitinib compared with carboplatin/paclitaxel on PFS (treatment by EGFR gene copy number interaction test P = .044; Fig 3A). In patients with high EGFR gene copy number (fluorescent in situ hybridization scores 5 and 6; n = 249), PFS was significantly longer with gefitinib versus carboplatin/paclitaxel (HR, 0.66; 95% CI, 0.50 to 0.88; P = .005). ORR also significantly favored gefitinib in these patients (58.9% v 44.8% for gefitinib v carboplatin/paclitaxel, respectively; odds ratio [OR], 1.79; 95% CI, 1.08 to 2.96; P = .024). Conversely, in patients with low EGFR gene copy number (n = 157), PFS was numerically longer (HR, 1.24; 95% CI, 0.87 to 1.76; P = .237) and ORR was numerically higher (26.3% v 22.2%; OR, 0.80; 95% CI, 0.38 to 1.68; P = .558) with carboplatin/paclitaxel versus gefitinib.
A total of 190 patients (78%) with high EGFR gene copy number also harbored EGFR mutations. Of the 153 patients with low EGFR gene copy number, only 51 (33%) were also EGFR mutation positive. Post hoc analyses found that PFS was significantly shorter with gefitinib versus carboplatin/paclitaxel in patients with high EGFR gene copy number in the absence of a coexisting EGFR mutation (n = 55; HR, 3.85; 95% CI, 2.09 to 7.09), although patients with EGFR mutation achieved significantly longer PFS with gefitinib versus carboplatin/paclitaxel irrespective of whether they had high (HR, 0.48; 95% CI, 0.34 to 0.67; n = 190) or low (HR, 0.51; 95% CI, 0.25 to 1.04; n = 51) EGFR gene copy number (Figs 4A to 4D).
Fig 4. Kaplan-Meier curves for progression-free survival (PFS) by epidermal growth factor receptor (EGFR) mutation status and EGFR gene copy number. Hazard ratio (HR) < 1 implies a lower risk of progression/death for patients treated with gefitinib. (A) High EGFR gene copy number EGFR mutation–positive. (B) High EGFR gene copy number EGFR mutation–negative. (C) Low EGFR gene copy number EGFR mutation–positive. (D) Low EGFR gene copy number EGFR mutation–negative. (*) Cox analysis with covariates (performance status [0-1, 2], smoking history [never, light ex-smoker], and sex).
There was no differential treatment effect for OS by EGFR gene copy number (treatment by EGFR gene copy number interaction test P = .428). There was no significant difference in OS for gefitinib versus carboplatin/paclitaxel in patients with high EGFR gene copy number (104 and 95 events, respectively; HR, 1.03; 95% CI, 0.78 to 1.37; P = .816) or low EGFR gene copy number (67 and 62 events, respectively; HR, 1.30; 95% CI, 0.92 to 1.85; P = .137; Fig 3B).

EGFR Protein Expression

There was no differential treatment effect for PFS by EGFR protein expression (treatment by EGFR protein expression status interaction test P = .214; Fig 3A). PFS was significantly longer for gefitinib versus carboplatin/paclitaxel in patients with EGFR protein expression–positive tumors (HR, 0.73; 95% CI, 0.55 to 0.96; P = .024; n = 266). There was no significant difference in PFS between treatments in patients with EGFR protein expression–negative tumors (HR, 0.97; 95% CI, 0.64 to 1.48; P = .893; n = 99).
ORRs were similar between the gefitinib and carboplatin/paclitaxel groups for patients with either EGFR protein expression–positive (51.5% v 41.8%; OR, 1.49; 95% CI, 0.92 to 2.42; P = .109) or EGFR protein expression–negative (34.0% v 26.1%; OR, 1.44; 95% CI, 0.60 to 3.47; P = .415) tumors.
There was no significant difference in OS for gefitinib versus carboplatin/paclitaxel in patients with EGFR protein expression–positive (107 and 105 events, respectively; HR, 1.05; 95% CI, 0.80 to 1.37; P = .731) or EGFR protein expression–negative (46 and 37 events, respectively; HR, 1.09; 95% CI, 0.70 to 1.70; P = .692) tumors.

Activating EGFR Mutation Type

Of the 261 patients with EGFR mutation–positive tumors, 53.6% (n = 140) had tumors with exon 19 deletions, and 42.5% (n = 111) had exon 21 L858R mutations (Data Supplement); demography was generally similar between these groups (Data Supplement).
In post hoc analyses, PFS was significantly longer for gefitinib versus carboplatin/paclitaxel in both the exon 19 deletions (HR, 0.38; 95% CI, 0.26 to 0.56) and the exon 21 L858R mutation (HR, 0.55; 95% CI, 0.35 to 0.87; Figs 5A and 5B) subgroups. Within-treatment analysis indicated no significant difference in PFS with gefitinib in the exon 19 deletions versus exon 21 L858R mutation subgroup (HR, 0.78; 95% CI, 0.51 to 1.19). ORR was significantly higher with gefitinib (84.8%) versus carboplatin/paclitaxel (43.2%; OR, 7.23; 95% CI, 3.19 to 16.37) in the exon 19 deletions subgroup and higher (but not statistically significant) in the L858R subgroup (60.9% v 53.2%; OR, 1.41; 95% CI, 0.65 to 3.05).
Fig 5. Kaplan-Meier curves for progression-free survival (PFS) by epidermal growth factor receptor (EGFR) mutation type (intent-to-treat population). Hazard ratio (HR) < 1 implies a lower risk of progression/death for patients treated with gefitinib. (A) Exon 19 deletion. (B) L858R. (*) Cox analysis with covariates (performance status [0-1, 2], smoking history [never, light ex-smoker], and sex).

Discussion

Gefitinib showed similar OS to doublet chemotherapy with no significant difference in the overall population or in patients with EGFR mutation–positive or EGFR mutation–negative status. The significant treatment-related differences for PFS and ORR according to EGFR mutation status were not observed for OS. Although there may be other contributing factors, the subsequent treatments that patients received are likely to have confounded the true effect of the initial, randomized first-line treatment on OS. Of the EGFR mutation– positive subgroup randomly assigned to carboplatin/paclitaxel, 64.3% received EGFR TKIs postdiscontinuation. Fewer patients with unknown mutation status randomly assigned to carboplatin/paclitaxel received EGFR TKIs (47.5%) compared with patients with EGFR mutation–positive status (64.3%), which may potentially contribute to the numerical trend in favor of gefitinib in this subgroup; statistical significance at the traditional 5% level (P < .05) cannot be claimed because no adjustment was made for multiple testing. The First-SIGNAL study had a study design similar to that of IPASS23 and reported no significant difference in OS (primary end point) between gefitinib versus gemcitabine/cisplatin (overall population, 182 events; 59% maturity; mutation-positive HR, 0.82; 95% CI, 0.35 to 1.92; P = .648; median survival, 30.6 v 26.5 months, respectively). The randomized Japanese NEJ002 study also reported that OS did not differ significantly between gefitinib and carboplatin/paclitaxel in patients selected by EGFR mutation status (median survival, 30.5 v 23.6 months, respectively; P = .31), likely explained by treatment crossover.24
Although collection of tumor material was not mandatory or feasible in all patients, IPASS has the largest group of patients with EGFR mutation–positive tumors studied in a randomized controlled trial in NSCLC and has confirmed EGFR mutation to be the strongest predictive biomarker for the effect of gefitinib with a statistically significant interaction test for PFS. Patients with mutation-negative tumors have a poorer outcome in terms of PFS and ORR with gefitinib compared with carboplatin/paclitaxel, indicating that in the first-line setting, gefitinib should not be used in preference to doublet chemotherapy in patients with a negative mutation status.
Our findings were broadly consistent with those of previous first-line, single-arm studies of gefitinib in patients with EGFR mutation–positive tumors.2532 Recently, outcomes similar to those of IPASS among patients with EGFR mutation–positive tumors have been reported in two randomized phase III studies24,33 comparing first-line gefitinib with doublet chemotherapy, with PFS as the primary end point. The NEJ002 study prospectively randomly assigned 230 patients with EGFR mutation–positive tumors to gefitinib or carboplatin/paclitaxel. PFS favored gefitinib over carboplatin/paclitaxel (PFS HR, 0.30; 95% CI, 0.22 to 0.41; P < .001; median PFS, 10.8 v 5.4 months; tumor response rate, 73.7% v 30.7%, respectively; P < .001).24 The similarly designed West Japan Thoracic Oncology Group 3405 (WJTOG3405) study reported increased PFS with gefitinib over cisplatin/docetaxel in 172 patients with EGFR mutation–positive tumors (PFS HR, 0.49; 95% CI, 0.34 to 0.70; P < .001; median PFS, 9.2 v 6.3 months; 295 events; 95% maturity).33 Tumor response rates (n = 117) were 62.1% and 32.2%. In the First-SIGNAL study, PFS (secondary end point) increased with gefitinib compared with gemcitabine/cisplatin in 42 patients with EGFR mutation–positive tumors (PFS HR, 0.61; 95% CI, 0.31 to 1.22; P = .084; median PFS, 8.4 v 6.7 months).23 The OPTIMAL study compared erlotinib with gemcitabine/cisplatin in 154 patients with EGFR mutation–positive tumors and also reported a significant difference in PFS (HR, 0.16; 95% CI, 0.10 to 0.26; P = .001).34 The similarly designed European Tarceva versus Chemotherapy (EURTAC) study is ongoing. Therefore to date, including IPASS, five randomized studies have shown that EGFR TKIs offer significant benefits over standard chemotherapy in patients with EGFR mutation–positive tumors.
In IPASS, high EGFR gene copy number was predictive for the effect of gefitinib versus carboplatin/paclitaxel on PFS. The significantly longer PFS with gefitinib in patients with both high EGFR gene copy number and EGFR mutation–positive tumors was not observed in patients with high EGFR gene copy number without an accompanying mutation, suggesting that the apparent PFS benefit was driven by overlap with a coexisting EGFR mutation (77.6% of patients with high EGFR gene copy number also had EGFR mutation–positive tumors). Patients with EGFR mutation–positive tumors without accompanying high EGFR gene copy number showed longer PFS with gefitinib than with carboplatin/paclitaxel, suggesting that EGFR mutations determine the treatment outcomes independent of the status of EGFR gene copy number.
Post hoc analyses of PFS by EGFR mutation type showed that PFS was significantly longer for gefitinib than for carboplatin/paclitaxel in both the exon 19 deletions and exon 21 L858R subgroups, with a slightly greater advantage in the exon 19 deletions subgroup. First-line, single-arm studies35,36 have reported an increased response to EGFR TKIs in patients with exon 19 deletions v exon 21 L858R mutation. However, IPASS (HR, 0.78; 95% CI, 0.51 to 1.19), WJTOG3405 (HR, 1.13; 95% CI, 0.63 to 2.03; P = .681), and NEJ002 (11.5 v 10.8 months; P = .90) randomized phase III studies and the prospective phase II iTARGET study (P = .600) showed no significant difference in PFS for gefitinib between the exon 19 deletions and exon 21 L858R mutation subgroups.24,25,33
In summary, EGFR mutation was the strongest predictive biomarker for benefit of gefitinib over carboplatin/paclitaxel on PFS and ORR. Post hoc analyses suggested that the predictive value of EGFR gene copy number for PFS benefit with gefitinib was driven by the overlap of high EGFR gene copy number with a positive EGFR mutation status. Treatment-related differences for PFS seen in patients with a positive EGFR mutation status were not apparent for OS. The OS results were likely confounded by the high proportion of patients receiving different types of subsequent therapies and, in particular, crossing over to the alternative treatment.

Acknowledgment

We thank the patients and investigators for participation in this study; Sarah Lewis (Complete Medical Communications) for medical writing support funded by AstraZeneca; R. McCormack (AstraZeneca) for biomarker analyses; and C. Watkins, and S. Lockwood (AstraZeneca) for advice on statistics.
See accompanying editorial on page 2843; listen to the podcast by Dr Sequist on www.jco.org/podcast
Clinical trial information can be found for the following: NCT00322452.

Copyright © 2011 by the American Society of Clinical Oncology

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Interpretation of the Biomarker Analysis and Final Overall Survival Results from IPASS
Lecia Sequist


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Authors' Disclosures of Potential Conflicts of INTEREST

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: Emma L. Duffield, AstraZeneca (C); Yuri Rukazenkov, AstraZeneca (C); Georgina Speake, AstraZeneca (C); Haiyi Jiang, AstraZeneca (C); Alison A. Armour, AstraZeneca (C) Consultant or Advisory Role: Sumitra Thongprasert, AstraZeneca (C), Novartis (C), Pfizer (C); Swan-Swan Leong, AstraZeneca (C); James Chih-Hsin Yang, AstraZeneca (C); Tony S.K. Mok, AstraZeneca (C), Roche (C), Pfizer (C), Bristol-Myers Squibb (C), Abbott Laboratories (C), Eli Lilly (C), Boehringer Ingelheim (C) Stock Ownership: Emma L. Duffield, AstraZeneca; Yuri Rukazenkov, AstraZeneca; Georgina Speake, AstraZeneca; Haiyi Jiang, AstraZeneca; Alison A. Armour, AstraZeneca Honoraria: Masahiro Fukuoka, AstraZeneca, Chugai Pharmaceutical, Boehringer Ingelheim; Yi-Long Wu, AstraZeneca, Roche, Eli Lilly; Sumitra Thongprasert, AstraZeneca, Eli Lilly; Patrapim Sunpaweravong, AstraZeneca; Kazuhiko Nakagawa, AstraZeneca, Chugai Pharmaceutical, Bristol-Meyers Squibb; Da-Tong Chu, AstraZeneca; Ka-Fai To, AstraZeneca; James Chih-Hsin Yang, AstraZeneca; Tony S.K. Mok, AstraZeneca, Roche, Eli Lilly, Pfizer, Boehringer Ingelheim, Eisai Pharmaceuticals Research Funding: Sumitra Thongprasert, AstraZeneca, Roche, Pfizer, sanofi-aventis; Patrapim Sunpaweravong, AstraZeneca; Tony S.K. Mok, AstraZeneca Expert Testimony: None Other Remuneration: Swan-Swan Leong, AstraZeneca

References

1.
M Sato, DS Shames, AF Gazdar, etal: A translational view of the molecular pathogenesis of lung cancer J Thorac Oncol 2: 327– 343,2007
2.
S Sun, JH Schiller, AF Gazdar: Lung cancer in never smokers: A different disease Nat Rev Cancer 7: 778– 790,2007
3.
X Tang, H Shigematsu, BN Bekele, etal: EGFR tyrosine kinase domain mutations are detected in histologically normal respiratory epithelium in lung cancer patients Cancer Res 65: 7568– 7572,2005
4.
M Bhutani, AK Pathak, YH Fan, etal: Oral epithelium as a surrogate tissue for assessing smoking-induced molecular alterations in the lungs Cancer Prev Res (Phila) 1: 39– 44,2008
5.
M Fukuoka, S Yano, G Giaccone, etal: Multi-institutional randomized phase II trial of gefitinib for previously treated patients with advanced non-small-cell lung cancer (The IDEAL 1 Trial) [corrected] J Clin Oncol 21: 2237– 2246,2003
6.
MG Kris, RB Natale, RS Herbst, etal: 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
7.
N Thatcher, A Chang, P Parikh, etal: 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
8.
TJ Lynch, DW Bell, R Sordella, etal: 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
9.
JG Paez, PA Jänne, JC Lee, etal: EGFR mutations in lung cancer: Correlation with clinical response to gefitinib therapy Science 304: 1497– 1500,2004
10.
T Mitsudomi, Y Yatabe: Mutations of the epidermal growth factor receptor gene and related genes as determinants of epidermal growth factor receptor tyrosine kinase inhibitors sensitivity in lung cancer Cancer Sci 98: 1817– 1824,2007
11.
MS Tsao, A Sakurada, JC Cutz, etal: Erlotinib in lung cancer: Molecular and clinical predictors of outcome N Engl J Med 353: 133– 144,2005
12.
FR Hirsch, M Varella-Garcia, PA Bunn Jr, etal: 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
13.
JY Douillard, FA Shepherd, V Hirsh, etal: Molecular predictors of outcome with gefitinib and docetaxel in previously treated non-small-cell lung cancer: Data from the randomized phase III INTEREST trial J Clin Oncol 28: 744– 752,2010
14.
CQ Zhu, G da Cunha Santos, K Ding, etal: Role of KRAS and EGFR as biomarkers of response to erlotinib in National Cancer Institute of Canada Clinical Trials Group Study BR.21 J Clin Oncol 26: 4268– 4275,2008
15.
F Cappuzzo, FR Hirsch, E Rossi, etal: Epidermal growth factor receptor gene and protein and gefitinib sensitivity in non-small-cell lung cancer J Natl Cancer Inst 97: 643– 655,2005
16.
FR Hirsch, M Varella-Garcia, J McCoy, etal: Increased epidermal growth factor receptor gene copy number detected by fluorescence in situ hybridization associates with increased sensitivity to gefitinib in patients with bronchioloalveolar carcinoma subtypes: A Southwest Oncology Group study J Clin Oncol 23: 6838– 6845,2005
17.
G Goss, D Ferry, R Wierzbicki, etal: Randomized phase II study of gefitinib compared with placebo in chemotherapy-naive patients with advanced non-small-cell lung cancer and poor performance status J Clin Oncol 27: 2253– 2260,2009
18.
ES Kim, V Hirsh, T Mok, etal: Gefitinib versus docetaxel in previously treated non-small-cell lung cancer (INTEREST): A randomised phase III trial Lancet 372: 1809– 1818,2008
19.
TS Mok, YL Wu, S Thongprasert, etal: Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma N Engl J Med 361: 947– 957,2009
20.
LM McShane, DG Altman, W Sauerbrei, etal: Reporting recommendations for tumor marker prognostic studies (REMARK) J Natl Cancer Inst 97: 1180– 1184,2005
21.
D Whitcombe, J Theaker, SP Guy, etal: Detection of PCR products using self-probing amplicons and fluorescence Nat Biotechnol 17: 804– 807,1999
22.
CR Newton, A Graham, LE Heptinstall, etal: Analysis of any point mutation in DNA: The amplification refractory mutation system (ARMS) Nucleic Acids Res 17: 2503– 2516,1989
23.
JS Lee, K Park, SW Kim, etal: A randomized phase III study of gefitinib (IRESSA™) versus standard chemotherapy (gemcitabine plus cisplatin) as a first-line treatment for never-smokers with advanced or metastatic adenocarcinoma of the lung J Thorac Oncol 2009 4: suppl 1 abstr PRS.4
24.
M Maemondo, A Inoue, K Kobayashi, etal: Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR N Engl J Med 362: 2380– 2388,2010
25.
LV Sequist, RG Martins, D Spigel, etal: First-line gefitinib in patients with advanced non-small-cell lung cancer harboring somatic EGFR mutations J Clin Oncol 26: 2442– 2449,2008
26.
H Asahina, K Yamazaki, I Kinoshita, etal: A phase II trial of gefitinib as first-line therapy for advanced non-small-cell lung cancer with epidermal growth factor receptor mutations Br J Cancer 95: 998– 1004,2006
27.
A Inoue, T Suzuki, T Fukuhara, etal: Prospective Phase II study of gefitinib for chemotherapy-naive patients with advanced non-small-cell lung cancer with epidermal growth factor receptor gene mutations J Clin Oncol 24: 3340– 3346,2006
28.
K Sugio, H Uramoto, T Onitsuka, etal: Prospective phase II study of gefitinib in non-small cell lung cancer with epidermal growth factor receptor gene mutations Lung Cancer 64: 314– 318,2009
29.
N Sunaga, Y Tomizawa, N Yanagitani, etal: Phase II prospective study of the efficacy of gefitinib for the treatment of stage III/IV non-small-cell lung cancer with EGFR mutations, irrespective of previous chemotherapy Lung Cancer 56: 383– 389,2007
30.
A Sutani, Y Nagai, K Udagawa, etal: Gefitinib for non-small-cell lung cancer patients with epidermal growth factor receptor gene mutations screened by peptide nucleic acid-locked nucleic acid PCR clamp Br J Cancer 95: 1483– 1489,2006
31.
K Tamura, I Okamoto, T Kashii, etal: Multicentre prospective phase II trial of gefitinib for advanced non-small-cell lung cancer with epidermal growth factor receptor mutations: Results of the West Japan Thoracic Oncology Group trial (WJTOG0403) Br J Cancer 98: 907– 914,2008
32.
K Yoshida, Y Yatabe, JY Park, etal: Prospective validation for prediction of gefitinib sensitivity by epidermal growth factor receptor gene mutation in patients with non-small cell lung cancer J Thorac Oncol 2: 22– 28,2007
33.
T Mitsudomi, S Morita, Y Yatabe, etal: Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): An open label, randomised phase 3 trial Lancet Oncol 11: 121– 128,2010
34.
C Zhou, YL Wu, G Chen, etal: Efficacy results from the randomized phase III OPTIMAL (CTONG 0802) study comparing first-line erlotinib vs carboplatin plus gemcitabine in Chinese advanced NSCLC patients with EGFR activating mutations Ann Oncol 2010 21: suppl 8 abstr LBA13
35.
CH Yang, CJ Yu, JY Shih, etal: Specific EGFR mutations predict treatment outcome of stage IIIB/IV patients with chemotherapy-naive non-small-cell lung cancer receiving first-line gefitinib monotherapy J Clin Oncol 26: 2745– 2753,2008
36.
R Rosell, T Moran, C Queralt, etal: Screening for epidermal growth factor receptor mutations in lung cancer N Engl J Med 361: 958– 967,2009

Information & Authors

Information

Published In

Journal of Clinical Oncology
Pages: 2866 - 2874
PubMed: 21670455

History

Published online: June 13, 2011
Published in print: July 20, 2011

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Authors

Affiliations

Masahiro Fukuoka
From the Kinki University School of Medicine; AstraZeneca, Osaka, Japan; Guangdong General Hospital, Guangzhou; Cancer Hospital, Chinese Academy of Medical Sciences, Beijing; State Key Laboratory in Oncology in South China, Li Ka Shing Institute of Health Science and the Sir Y.K. Pao Center for Cancer, The Chinese University of Hong Kong, Hong Kong, China; Maharaj Nakorn ChiangMai Hospital, ChiangMai University, ChiangMai; Prince of Songkla University, Songkla; Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand; National Cancer Centre Singapore, Singapore; Tri-Service General Hospital; National Taiwan University Hospital and College of Medicine, Taipei, Taiwan; and AstraZeneca, Macclesfield, United Kingdom.
Yi-Long Wu
From the Kinki University School of Medicine; AstraZeneca, Osaka, Japan; Guangdong General Hospital, Guangzhou; Cancer Hospital, Chinese Academy of Medical Sciences, Beijing; State Key Laboratory in Oncology in South China, Li Ka Shing Institute of Health Science and the Sir Y.K. Pao Center for Cancer, The Chinese University of Hong Kong, Hong Kong, China; Maharaj Nakorn ChiangMai Hospital, ChiangMai University, ChiangMai; Prince of Songkla University, Songkla; Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand; National Cancer Centre Singapore, Singapore; Tri-Service General Hospital; National Taiwan University Hospital and College of Medicine, Taipei, Taiwan; and AstraZeneca, Macclesfield, United Kingdom.
Sumitra Thongprasert
From the Kinki University School of Medicine; AstraZeneca, Osaka, Japan; Guangdong General Hospital, Guangzhou; Cancer Hospital, Chinese Academy of Medical Sciences, Beijing; State Key Laboratory in Oncology in South China, Li Ka Shing Institute of Health Science and the Sir Y.K. Pao Center for Cancer, The Chinese University of Hong Kong, Hong Kong, China; Maharaj Nakorn ChiangMai Hospital, ChiangMai University, ChiangMai; Prince of Songkla University, Songkla; Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand; National Cancer Centre Singapore, Singapore; Tri-Service General Hospital; National Taiwan University Hospital and College of Medicine, Taipei, Taiwan; and AstraZeneca, Macclesfield, United Kingdom.
Patrapim Sunpaweravong
From the Kinki University School of Medicine; AstraZeneca, Osaka, Japan; Guangdong General Hospital, Guangzhou; Cancer Hospital, Chinese Academy of Medical Sciences, Beijing; State Key Laboratory in Oncology in South China, Li Ka Shing Institute of Health Science and the Sir Y.K. Pao Center for Cancer, The Chinese University of Hong Kong, Hong Kong, China; Maharaj Nakorn ChiangMai Hospital, ChiangMai University, ChiangMai; Prince of Songkla University, Songkla; Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand; National Cancer Centre Singapore, Singapore; Tri-Service General Hospital; National Taiwan University Hospital and College of Medicine, Taipei, Taiwan; and AstraZeneca, Macclesfield, United Kingdom.
Swan-Swan Leong
From the Kinki University School of Medicine; AstraZeneca, Osaka, Japan; Guangdong General Hospital, Guangzhou; Cancer Hospital, Chinese Academy of Medical Sciences, Beijing; State Key Laboratory in Oncology in South China, Li Ka Shing Institute of Health Science and the Sir Y.K. Pao Center for Cancer, The Chinese University of Hong Kong, Hong Kong, China; Maharaj Nakorn ChiangMai Hospital, ChiangMai University, ChiangMai; Prince of Songkla University, Songkla; Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand; National Cancer Centre Singapore, Singapore; Tri-Service General Hospital; National Taiwan University Hospital and College of Medicine, Taipei, Taiwan; and AstraZeneca, Macclesfield, United Kingdom.
Virote Sriuranpong
From the Kinki University School of Medicine; AstraZeneca, Osaka, Japan; Guangdong General Hospital, Guangzhou; Cancer Hospital, Chinese Academy of Medical Sciences, Beijing; State Key Laboratory in Oncology in South China, Li Ka Shing Institute of Health Science and the Sir Y.K. Pao Center for Cancer, The Chinese University of Hong Kong, Hong Kong, China; Maharaj Nakorn ChiangMai Hospital, ChiangMai University, ChiangMai; Prince of Songkla University, Songkla; Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand; National Cancer Centre Singapore, Singapore; Tri-Service General Hospital; National Taiwan University Hospital and College of Medicine, Taipei, Taiwan; and AstraZeneca, Macclesfield, United Kingdom.
Tsu-Yi Chao
From the Kinki University School of Medicine; AstraZeneca, Osaka, Japan; Guangdong General Hospital, Guangzhou; Cancer Hospital, Chinese Academy of Medical Sciences, Beijing; State Key Laboratory in Oncology in South China, Li Ka Shing Institute of Health Science and the Sir Y.K. Pao Center for Cancer, The Chinese University of Hong Kong, Hong Kong, China; Maharaj Nakorn ChiangMai Hospital, ChiangMai University, ChiangMai; Prince of Songkla University, Songkla; Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand; National Cancer Centre Singapore, Singapore; Tri-Service General Hospital; National Taiwan University Hospital and College of Medicine, Taipei, Taiwan; and AstraZeneca, Macclesfield, United Kingdom.
Kazuhiko Nakagawa
From the Kinki University School of Medicine; AstraZeneca, Osaka, Japan; Guangdong General Hospital, Guangzhou; Cancer Hospital, Chinese Academy of Medical Sciences, Beijing; State Key Laboratory in Oncology in South China, Li Ka Shing Institute of Health Science and the Sir Y.K. Pao Center for Cancer, The Chinese University of Hong Kong, Hong Kong, China; Maharaj Nakorn ChiangMai Hospital, ChiangMai University, ChiangMai; Prince of Songkla University, Songkla; Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand; National Cancer Centre Singapore, Singapore; Tri-Service General Hospital; National Taiwan University Hospital and College of Medicine, Taipei, Taiwan; and AstraZeneca, Macclesfield, United Kingdom.
Da-Tong Chu
From the Kinki University School of Medicine; AstraZeneca, Osaka, Japan; Guangdong General Hospital, Guangzhou; Cancer Hospital, Chinese Academy of Medical Sciences, Beijing; State Key Laboratory in Oncology in South China, Li Ka Shing Institute of Health Science and the Sir Y.K. Pao Center for Cancer, The Chinese University of Hong Kong, Hong Kong, China; Maharaj Nakorn ChiangMai Hospital, ChiangMai University, ChiangMai; Prince of Songkla University, Songkla; Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand; National Cancer Centre Singapore, Singapore; Tri-Service General Hospital; National Taiwan University Hospital and College of Medicine, Taipei, Taiwan; and AstraZeneca, Macclesfield, United Kingdom.
Nagahiro Saijo
From the Kinki University School of Medicine; AstraZeneca, Osaka, Japan; Guangdong General Hospital, Guangzhou; Cancer Hospital, Chinese Academy of Medical Sciences, Beijing; State Key Laboratory in Oncology in South China, Li Ka Shing Institute of Health Science and the Sir Y.K. Pao Center for Cancer, The Chinese University of Hong Kong, Hong Kong, China; Maharaj Nakorn ChiangMai Hospital, ChiangMai University, ChiangMai; Prince of Songkla University, Songkla; Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand; National Cancer Centre Singapore, Singapore; Tri-Service General Hospital; National Taiwan University Hospital and College of Medicine, Taipei, Taiwan; and AstraZeneca, Macclesfield, United Kingdom.
Emma L. Duffield
From the Kinki University School of Medicine; AstraZeneca, Osaka, Japan; Guangdong General Hospital, Guangzhou; Cancer Hospital, Chinese Academy of Medical Sciences, Beijing; State Key Laboratory in Oncology in South China, Li Ka Shing Institute of Health Science and the Sir Y.K. Pao Center for Cancer, The Chinese University of Hong Kong, Hong Kong, China; Maharaj Nakorn ChiangMai Hospital, ChiangMai University, ChiangMai; Prince of Songkla University, Songkla; Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand; National Cancer Centre Singapore, Singapore; Tri-Service General Hospital; National Taiwan University Hospital and College of Medicine, Taipei, Taiwan; and AstraZeneca, Macclesfield, United Kingdom.
Yuri Rukazenkov
From the Kinki University School of Medicine; AstraZeneca, Osaka, Japan; Guangdong General Hospital, Guangzhou; Cancer Hospital, Chinese Academy of Medical Sciences, Beijing; State Key Laboratory in Oncology in South China, Li Ka Shing Institute of Health Science and the Sir Y.K. Pao Center for Cancer, The Chinese University of Hong Kong, Hong Kong, China; Maharaj Nakorn ChiangMai Hospital, ChiangMai University, ChiangMai; Prince of Songkla University, Songkla; Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand; National Cancer Centre Singapore, Singapore; Tri-Service General Hospital; National Taiwan University Hospital and College of Medicine, Taipei, Taiwan; and AstraZeneca, Macclesfield, United Kingdom.
Georgina Speake
From the Kinki University School of Medicine; AstraZeneca, Osaka, Japan; Guangdong General Hospital, Guangzhou; Cancer Hospital, Chinese Academy of Medical Sciences, Beijing; State Key Laboratory in Oncology in South China, Li Ka Shing Institute of Health Science and the Sir Y.K. Pao Center for Cancer, The Chinese University of Hong Kong, Hong Kong, China; Maharaj Nakorn ChiangMai Hospital, ChiangMai University, ChiangMai; Prince of Songkla University, Songkla; Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand; National Cancer Centre Singapore, Singapore; Tri-Service General Hospital; National Taiwan University Hospital and College of Medicine, Taipei, Taiwan; and AstraZeneca, Macclesfield, United Kingdom.
Haiyi Jiang
From the Kinki University School of Medicine; AstraZeneca, Osaka, Japan; Guangdong General Hospital, Guangzhou; Cancer Hospital, Chinese Academy of Medical Sciences, Beijing; State Key Laboratory in Oncology in South China, Li Ka Shing Institute of Health Science and the Sir Y.K. Pao Center for Cancer, The Chinese University of Hong Kong, Hong Kong, China; Maharaj Nakorn ChiangMai Hospital, ChiangMai University, ChiangMai; Prince of Songkla University, Songkla; Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand; National Cancer Centre Singapore, Singapore; Tri-Service General Hospital; National Taiwan University Hospital and College of Medicine, Taipei, Taiwan; and AstraZeneca, Macclesfield, United Kingdom.
Alison A. Armour
From the Kinki University School of Medicine; AstraZeneca, Osaka, Japan; Guangdong General Hospital, Guangzhou; Cancer Hospital, Chinese Academy of Medical Sciences, Beijing; State Key Laboratory in Oncology in South China, Li Ka Shing Institute of Health Science and the Sir Y.K. Pao Center for Cancer, The Chinese University of Hong Kong, Hong Kong, China; Maharaj Nakorn ChiangMai Hospital, ChiangMai University, ChiangMai; Prince of Songkla University, Songkla; Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand; National Cancer Centre Singapore, Singapore; Tri-Service General Hospital; National Taiwan University Hospital and College of Medicine, Taipei, Taiwan; and AstraZeneca, Macclesfield, United Kingdom.
Ka-Fai To
From the Kinki University School of Medicine; AstraZeneca, Osaka, Japan; Guangdong General Hospital, Guangzhou; Cancer Hospital, Chinese Academy of Medical Sciences, Beijing; State Key Laboratory in Oncology in South China, Li Ka Shing Institute of Health Science and the Sir Y.K. Pao Center for Cancer, The Chinese University of Hong Kong, Hong Kong, China; Maharaj Nakorn ChiangMai Hospital, ChiangMai University, ChiangMai; Prince of Songkla University, Songkla; Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand; National Cancer Centre Singapore, Singapore; Tri-Service General Hospital; National Taiwan University Hospital and College of Medicine, Taipei, Taiwan; and AstraZeneca, Macclesfield, United Kingdom.
James Chih-Hsin Yang
From the Kinki University School of Medicine; AstraZeneca, Osaka, Japan; Guangdong General Hospital, Guangzhou; Cancer Hospital, Chinese Academy of Medical Sciences, Beijing; State Key Laboratory in Oncology in South China, Li Ka Shing Institute of Health Science and the Sir Y.K. Pao Center for Cancer, The Chinese University of Hong Kong, Hong Kong, China; Maharaj Nakorn ChiangMai Hospital, ChiangMai University, ChiangMai; Prince of Songkla University, Songkla; Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand; National Cancer Centre Singapore, Singapore; Tri-Service General Hospital; National Taiwan University Hospital and College of Medicine, Taipei, Taiwan; and AstraZeneca, Macclesfield, United Kingdom.
Tony S.K. Mok [email protected]
From the Kinki University School of Medicine; AstraZeneca, Osaka, Japan; Guangdong General Hospital, Guangzhou; Cancer Hospital, Chinese Academy of Medical Sciences, Beijing; State Key Laboratory in Oncology in South China, Li Ka Shing Institute of Health Science and the Sir Y.K. Pao Center for Cancer, The Chinese University of Hong Kong, Hong Kong, China; Maharaj Nakorn ChiangMai Hospital, ChiangMai University, ChiangMai; Prince of Songkla University, Songkla; Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand; National Cancer Centre Singapore, Singapore; Tri-Service General Hospital; National Taiwan University Hospital and College of Medicine, Taipei, Taiwan; and AstraZeneca, Macclesfield, United Kingdom.

Notes

Corresponding author: Tony S.K. Mok, MD, The Chinese University of Hong Kong, 22D Union Court, 18 Fu Kin Street, Shatin, Hong Kong, China; e-mail: [email protected].

Author Contributions

Conception and design: Masahiro Fukuoka, Sumitra Thongprasert, Nagahiro Saijo, Haiyi Jiang, Alison A. Armour, Ka-Fai To, James Chih-Hsin Yang, Tony S.K. Mok
Provision of study materials or patients: Yi-Long Wu, Swan-Swan Leong, Virote Sriuranpong, Ka-Fai To
Collection and assembly of data: Yi-Long Wu, Sumitra Thongprasert, Patrapim Sunpaweravong, Swan-Swan Leong, Virote Sriuranpong, Tsu-Yi Chao, Da-Tong Chu, Yuri Rukazenkov, Haiyi Jiang, Alison A. Armour, James Chih-Hsin Yang, Tony S.K. Mok
Data analysis and interpretation: Sumitra Thongprasert, Kazuhiko Nakagawa, Emma L. Duffield, Yuri Rukazenkov, Georgina Speake, Haiyi Jiang, Alison A. Armour, James Chih-Hsin Yang, Tony S.K. Mok
Manuscript writing: All authors
Final approval of manuscript: All authors

Disclosures

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

Funding Information

Supported by AstraZeneca.

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Masahiro Fukuoka, Yi-Long Wu, Sumitra Thongprasert, Patrapim Sunpaweravong, Swan-Swan Leong, Virote Sriuranpong, Tsu-Yi Chao, Kazuhiko Nakagawa, Da-Tong Chu, Nagahiro Saijo, Emma L. Duffield, Yuri Rukazenkov, Georgina Speake, Haiyi Jiang, Alison A. Armour, Ka-Fai To, James Chih-Hsin Yang, Tony S.K. Mok
Journal of Clinical Oncology 2011 29:21, 2866-2874

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