- © 2012 by American Society of Clinical Oncology
Vandetanib Versus Placebo in Patients With Advanced Non–Small-Cell Lung Cancer After Prior Therapy With an Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor: A Randomized, Double-Blind Phase III Trial (ZEPHYR)
- Jin Soo Lee⇓,
- Vera Hirsh,
- Keunchil Park,
- Shukui Qin,
- Cesar R. Blajman,
- Reury-Perng Perng,
- Yuh-Min Chen,
- Laura Emerson,
- Peter Langmuir and
- Christian Manegold
- Jin Soo Lee, National Cancer Center, Goyang; Keunchil Park, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea; Vera Hirsh, McGill University Health Centre, Montreal, Quebec, Canada; Shukui Qin, Nanjing Bayi Hospital, Nanjing, China; Cesar R. Blajman, Isis Centro Especializado, Santa Fe, Argentina; Reury-Perng Perng, Veterans General Hospital; Yuh-Min Chen, Veterans General Hospital, and School of Medicine, National Yang-Ming University, Taipei, Taiwan; Laura Emerson, AstraZeneca, Loughborough, United Kingdom; Peter Langmuir, AstraZeneca, Wilmington, DE; and Christian Manegold, University Medical Center, Mannheim, Germany.
- Corresponding author: Jin Soo Lee, MD, Center for Lung Cancer, National Cancer Center, 111 Jungbalsan-ro, Ilsandong-gu, Goyang 410-769, South Korea; e-mail: jslee{at}ncc.re.kr.
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Presented in part at the 46th Annual Meeting of the American Society of Clinical Oncology, June 4-8, 2010, Chicago, IL.
Abstract
Purpose Vandetanib is a once-daily oral inhibitor of vascular endothelial growth factor receptor, epidermal growth factor receptor (EGFR), and RET signaling. This placebo-controlled trial assessed whether vandetanib conferred an overall survival benefit in patients with advanced non–small-cell lung cancer (NSCLC) after prior treatment with an EGFR tyrosine kinase inhibitor and one or two chemotherapy regimens.
Patients and Methods Eligible patients were randomly assigned 2:1 to receive vandetanib 300 mg/d or placebo until disease progression or unacceptable toxicity. The primary objective was to compare the outcomes between the two arms with respect to overall survival.
Results Overall, 924 patients received vandetanib (n = 617) or placebo (n = 307). No significant increase in overall survival was detected in the vandetanib cohort compared with placebo (hazard ratio = 0.95; 95.2% CI, 0.81 to 1.11; P = .527); median overall survival was 8.5 months versus 7.8 months for vandetanib and placebo patients, respectively. Statistically significant advantages favoring vandetanib were observed for progression-free survival (hazard ratio = 0.63; P < .001) and objective response rate (2.6% v 0.7%; P = .028). Postprogression therapy was balanced across the cohorts in both number and type. Adverse events were generally consistent with previous NSCLC studies of vandetanib 300 mg; common events occurring with a greater frequency in the vandetanib arm versus placebo included diarrhea (46% v 11%), rash (42% v 11%), and hypertension (26% v 3%).
Conclusion The study did not demonstrate an overall survival benefit for vandetanib versus placebo. There was a higher incidence of some adverse events with vandetanib.
INTRODUCTION
Lung cancer is the most common cause of cancer death worldwide, with an estimated 1.18 million deaths reported annually and a dismal 5-year-survival rate of 9% to 15%.1 The epidermal growth factor receptor (EGFR) is now an established therapeutic target in non–small-cell lung cancer (NSCLC). The EGFR tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib have demonstrated single-agent activity in previously treated NSCLC2,3 and in the first-line setting in selected patients with EGFR mutations.4,5 However, effective treatments are needed for patients with advanced NSCLC who experience disease progression after treatment with EGFR TKIs. Resistance to anti-EGFR therapy may be a consequence of increased vascular endothelial growth factor (VEGF) expression,6,7 which supports the rationale for combined targeting of VEGF receptor (VEGFR) and EGFR signaling.
Vandetanib is a once-daily, oral anticancer TKI that selectively targets VEGFR, EGFR, and RET (rearranged during transfection).8–10 In patients with previously treated advanced NSCLC, a series of phase II and III trials have confirmed that vandetanib is an active agent, both as a monotherapy11,12 and in combination with certain chemotherapeutic agents.13–15 Studies in clinically relevant xenograft models of human NSCLC have also shown that vandetanib can abrogate both primary and acquired resistance to EGFR TKIs.16
This randomized, placebo-controlled, phase III study (ZEPHYR [Zactima Efficacy Trial for NSCLC Patients With History of EGFR-TKI and Chemoresistance]) assessed whether vandetanib 300 mg/d confers an overall survival benefit in patients with locally advanced or metastatic NSCLC who have received one or two previous chemotherapy regimens and have experienced treatment failure with an EGFR TKI.
PATIENTS AND METHODS
Patient Eligibility
Eligible patients were adults with locally advanced or metastatic (stage IIIB or IV) NSCLC who had received one or two prior chemotherapy regimens and had experienced treatment failure with an EGFR TKI (because of radiologic documentation of disease progression or toxicity). Inclusion criteria included a WHO performance status of 0 to 2, a life expectancy of at least 12 weeks, measurable disease according to RECIST (Response Evaluation Criteria In Solid Tumors), and no significant hematologic, hepatic, renal, or cardiac abnormalities. Patients with squamous cell histology were eligible, as were patients with brain metastases, provided that they received treatment at least 4 weeks before study entry and were clinically stable without corticosteroid treatment for a minimum of 10 days. Patients were excluded if they had received three or more chemotherapy regimens and if they had received any chemotherapy or radiation therapy within 4 weeks or EGFR TKIs within 3 weeks of study entry. Previous treatment with a VEGFR TKI was not permitted, although prior treatment with bevacizumab was allowed. The trial was approved by all relevant institutional ethical committees or review bodies and was conducted in accordance with the Declaration of Helsinki, Good Clinical Practice, and the AstraZeneca policy on bioethics. All patients provided written informed consent.
Study Design and Treatments
In this multicenter, randomized, double-blind, placebo-controlled, phase III study, patients were randomly assigned 2:1 to receive vandetanib 300 mg/d or placebo until disease progression, unacceptable toxicity, or withdrawal of consent. Both treatment groups received best supportive care in accordance with local clinical practice. The primary objective was to compare the outcomes between the two arms with respect to overall survival. The secondary end points for the study included progression-free survival (PFS), objective response rate, time to deterioration of symptoms (TDS), and safety and tolerability. An exploratory objective was to investigate the potential correlation between efficacy and tumor- and blood-based biomarkers. Radiologic evaluation (RECIST, version 1.0) was performed at baseline and every 8 weeks after randomization until objective disease progression was observed.
Patient-reported TDS was calculated using the seven-item Lung Cancer Subscale (LCS) score from the Functional Assessment of Cancer Therapy for Lung Cancer (FACT-L) questionnaire17 combined with pain and fatigue scores (nine items in total; LCS-PF). Each item was scored on a 5-point scale (range of scores, 0 to 36). Questionnaires were scheduled for completion at baseline (within 7 days of starting treatment), every 4 weeks after randomization, at discontinuation of study treatment, and 30 days after discontinuation. Deterioration was predefined as an adverse change of ≥ 3 points from baseline with no improvement in the next 21 days; this has been shown to be a clinically meaningful change in patients with advanced NSCLC.18
Safety assessments were based on adverse events, laboratory data, ECG data, vital signs, and body weight. Adverse events were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE, version 3.0). Scheduled 12-lead ECGs were performed during screening; at 1, 2, 4, 8, 12, and 16 weeks after starting randomized treatment; and every 3 months thereafter. The QTc interval was evaluated centrally, and prolongation was defined as described previously.19 Management of adverse events generally consisted of dose interruption followed by dose reduction as necessary. Safety was monitored for 60 days after the last dose of study treatment.
The following prespecified analyses were performed on archival tumor samples collected from consenting patients: EGFR protein expression by immunohistochemistry (DAKO antibody; EGFR positive required ≥ 10% of tumor cells demonstrating EGFR staining; DAKO, Copenhagen, Denmark), EGFR gene copy number by fluorescent in situ hybridization (FISH; Abbott Vysis, Abbott Park, IL) with FISH status (±) determined using the Colorado scoring system,20 and EGFR and KRAS gene mutation status (wild type or mutation) by the amplification refractory mutation system (ARMS) assay (DxS EGFR 29 mutation kit [exons 18 to 21]; DxS KRAS 7 mutation kit [exons 12-13]).
Baseline plasma concentrations of VEGF, VEGFR-2, and basic fibroblast growth factor (bFGF) were determined by enzyme-linked immunosorbent assay as described previously.21 Cutoff values in this study were as follows: VEGF (low, ≤ 55.0 pg/mL; high, > 55.0 pg/mL); VEGFR-2 (low, ≤ 9,881.65 pg/mL; high > 9,881.65 pg/mL); bFGF (low, ≤ 2.10 pg/mL; high > 2.10 pg/mL). These cutoffs were based on reference values determined in healthy volunteers, as described in the manufacturer's instructions (R&D Systems Quantikine Immunoassays, Minneapolis, MN). For VEGF, assay values within the normal enzyme-linked immunosorbent assay reference range (0 to 55 pg/mL) were classified as low, with values above classified as high. For VEGFR-2 and bFGF, assay values at or below the median (VEGFR-2, 9,881.65 pg/mL; bFGF, 2.10 pg/mL) were classified as low, with values above classified as high.
Statistical Analysis
To detect a 33% prolongation in overall survival (ie, ≥ 25% reduction in the death rate; hazard ratio, ≤ 0.75) with ≥ 90% power (β ≤ .10) the final analysis of overall survival was performed by the study sponsor when a minimum of 690 deaths had occurred. To allow for a single interim analysis (performed by the Independent Statistical Data Analysis Centre), the nominal two-sided significance level of 5% was adjusted to approximately 4.8% (α = .048) for overall survival and PFS. Overall survival, PFS, and TDS were analyzed using the log-rank test (unadjusted model with treatment factor only). A secondary analysis of overall survival and PFS using a Cox proportional hazards regression model allowed for the effect of treatment and included terms for tumor stage, number of organs involved, histology, WHO performance status at baseline, smoking history, sex, ethnic origin, prior EGFR TKI therapy, EGFR expression, EGFR gene amplification, and EGFR mutation status. For the Cox proportional hazards model, a global interaction test was performed to determine any treatment by covariate interactions. The objective response rate was analyzed using logistic regression. Patient stratification was only by center.
RESULTS
Patient Baseline Characteristics
Between November 2006 and November 2008, 924 patients were randomly assigned (2:1) to receive treatment with vandetanib (n = 617) or placebo (n = 307; Fig 1). Baseline demographics and patient characteristics were similar in the two treatment groups (Table 1), including best response to the most recent EGFR TKI treatment before study entry. In total, 53% of patients were female, 53% were never smokers, and 39% were white. The majority of patients (58%) entering the trial had received three previous lines of systemic treatment (two previous chemotherapy regimens and an EGFR TKI), and the median duration of the previous EGFR TKI treatment was 165 and 152 days in the vandetanib and placebo cohorts, respectively.
Trial profile.
Baseline Demographics and Patient Characteristics in the Full Analysis Set (all randomly assigned patients)
At data cutoff (October 19, 2009), the median duration of follow-up was 15.4 and 15.6 months for the vandetanib and placebo cohorts, respectively. The number of patients experiencing disease progression was 553 (89.6%) in the vandetanib cohort and 281 (91.5%) in the placebo cohort, with 471 (76.3%) and 234 (76.2%) deaths recorded in the vandetanib and placebo cohorts, respectively. Postprogression therapy was balanced across the two cohorts in terms of number of patients receiving therapy and type of therapy received; subsequent anticancer therapy was received by 52.0% of vandetanib-treated patients and 59.6% of placebo patients.
Efficacy
The primary end point of overall survival showed no statistically significant difference between patients receiving vandetanib or placebo (hazard ratio = 0.95; 95.2% CI, 0.81 to 1.11; P = .527); median overall survival was 8.5 months with vandetanib and 7.8 months with placebo (Fig 2A). The estimated percentage of vandetanib patients alive after 1 year was 35.5% versus 31.7% for placebo.
Kaplan-Meier estimates of (A) overall survival and (B) progression-free survival in the full analysis set (all randomly assigned patients) at the time of data cutoff. HR, hazard ratio.
Patients randomly assigned to vandetanib showed a statistically significant advantage in the secondary end point of PFS (hazard ratio = 0.63; 95.2% CI, 0.54 to 0.74; P < .001); median PFS was 1.9 months with vandetanib and 1.8 months with placebo, although these single-point estimates do not seem to represent the difference between treatments seen across the entire Kaplan-Meier curve (Fig 2B). Statistically significant advantages favoring vandetanib were also seen for the objective response rate (2.6% [n = 16] v 0.7% [n = 2]; P = .028). All objective responses were confirmed partial responses.
A global interaction test to assess the interaction between treatment and a preplanned set of clinical and demographic covariates was performed for overall survival (Fig 3A) and repeated for PFS (Fig 3B). Neither test was significant, indicating that the effect of treatment was generally consistent across the clinical and demographic covariates. However, inspection of the results for individual subgroups suggested a differential PFS benefit with vandetanib for females versus males, patients of East Asian origin versus whites, never smokers versus smokers, patients with adenocarcinoma versus squamous histology, and patients previously treated with gefitinib versus erlotinib; no such patterns were seen for overall survival.
Hazard ratios for (A) overall survival and (B) progression-free survival in preplanned clinical and demographic subgroup analyses of the full analysis set (all randomly assigned patients). A hazard ratio less than 1 favors vandetanib. Analyses were performed using a log-rank test with treatment as the only factor. PS, performance status.
There was no evidence that baseline tumor biomarker status (EGFR expression, EGFR gene amplification, or EGFR or KRAS gene mutation) had a differential impact on overall survival (Fig 4A). In terms of PFS, a greater benefit was suggested for vandetanib-treated patients with a positive EGFR mutation status compared with a negative EGFR mutation status (Fig 4B). However, more than 75% of patients had an unknown status, owing to missing or poor-quality tumor samples.
Hazard ratios for (A, C) overall survival and (B, D) progression-free survival in preplanned subgroup analyses of the full analysis set (all randomly assigned patients). (A, B) Tumor biomarker subgroups. (C, D) Blood biomarker subgroups. A hazard ratio less than 1 favors vandetanib. Analyses were performed using a log-rank test with treatment as the only factor. bFGF, basic fibroblast growth factor; VEGF, vascular endothelial growth factor; VEGFR2, vascular endothelial growth factor receptor 2.
The baseline status of plasma biomarkers (VEGF, VEGFR-2, and bFGF) was determined in more than 85% of patients in each treatment arm. The only statistically significant difference in overall survival with respect to plasma biomarkers was in patients with low baseline plasma levels of VEGF (hazard ratio = 0.66; P = .023; Fig 4C); although this finding may be due to chance, it seems warranted to further explore its utility as a surrogate biomarker for vandetanib efficacy. There was no evidence that plasma biomarker status had a differential impact on PFS (Fig 4D).
Patient-Reported Outcomes
The compliance rate for the FACT-L questionnaire was 86.1% and 84.7% for the vandetanib and placebo cohorts, respectively. There was no significant difference in TDS (LCS-PF) between patients receiving vandetanib or placebo (hazard ratio = 0.98; 95% CI, 0.82 to 1.16; P = .799).
Safety and Tolerability
The mean duration of treatment exposure was 14.4 weeks for vandetanib and 10.7 weeks for placebo, which probably reflects the PFS advantage in the vandetanib arm. The median duration of exposure was similar in both cohorts (vandetanib, 8.4 weeks; placebo, 8.0 weeks).
diarrhea (n = 287, 46.4%), rash (n = 262, 42.3%), and hypertension (n = 164, 26.5%) were the most frequently reported adverse events in the vandetanib cohort, and the incidence of all three was at least 20% higher than in the placebo cohort (Table 2). These were also the most common adverse events of grade 3 or worse (Table 3). The incidence of protocol-defined QTc prolongation was 6.5% (n = 40) in patients receiving vandetanib versus 1.0% (n = 3) in patients receiving placebo. No patient had a reported symptomatic QTc prolongation or an adverse event of torsade de pointes. A larger proportion of patients in the vandetanib cohort (n = 161, 26.0%) had a dose reduction or interruption compared with the placebo cohort (n = 14, 4.6%). The most frequently reported adverse events in the vandetanib arm leading to dose reduction were diarrhea (1.6%), rash (1.3%), and QTc prolongation (1.3%); the most frequent leading to dose interruption were QTc prolongation (3.1%), diarrhea (2.9%), rash (2.6%), and hypertension (2.1%). The median time to first dose interruption of vandetanib was 5.4 weeks, and dose interruptions led to a mean time of approximately 1.5 weeks off treatment. Events of QTc prolongation were successfully managed by short dose interruption or dose reduction as per the management plan and led to permanent discontinuation of treatment in only two patients (0.3%). Adverse events leading to treatment discontinuation were more frequent with vandetanib (n = 75, 12.1%) than with placebo (n = 16, 5.3%). rash (n = 11, 1.8%) was the most common adverse event leading to vandetanib discontinuation.
Adverse Events Reported in ≥ 10% of Patients in Either Cohort (safety population*)
Grade ≥ 3 Adverse Events Reported in ≥ 2% of Patients in Either Treatment Arm (safety population*), Arranged by System Organ Class
Serious adverse events were reported more frequently with vandetanib (n = 160, 25.8%) versus placebo (n = 63, 20.8%). The most common serious adverse events in both cohorts were respiratory events and chest infections, which is consistent with the clinical presentation of patients with advanced, heavily pretreated NSCLC. The incidence of death resulting from serious adverse events was low and similar in both arms (3.9%, vandetanib; 4.0%, placebo), with respiratory events being the most common cause. In both cohorts, the majority of deaths were related to lung cancer.
Clinical laboratory results revealed that median hemoglobin levels were consistently higher (by approximately 10 g/L) in patients receiving vandetanib, which was reflected in the lower incidence of anemia reported with vandetanib versus placebo: all grades (3.1% v 6.9%) and grade ≥3 (0.8% v 2.3%). Median transaminase levels were also consistently higher in vandetanib patients; during study treatment, 27 patients (4.4%) in the vandetanib cohort had an ALT level three times higher than the upper limit of normal compared with three patients (1.0%) in the placebo arm. A larger proportion of vandetanib patients had elevations in blood pressure (BP); 235 (38.0%) receiving vandetanib and 31 (10.2%) receiving placebo experienced at least one assessment of systolic BP more than 160 mmHg or diastolic BP more than 100 mmHg or a diastolic BP change from baseline of more than 20 mmHg. However, there was no evidence of an increased incidence of cardiac or cerebrovascular ischemia in vandetanib-treated patients who developed newly elevated bp during the study. There were no other clinically significant abnormalities or important differences in laboratory parameters between treatment arms.
DISCUSSION
This randomized, placebo-controlled, phase III study investigated the efficacy of vandetanib, an inhibitor of VEGFR and EGFR signaling, in patients with advanced NSCLC who have failed prior chemotherapy and who have experienced disease progression after treatment with an EGFR TKI. There is currently no approved treatment option for this patient population.
The primary end point of overall survival was not different between patients receiving vandetanib as compared with those receiving placebo. In both cohorts, median overall survival (8.5 months with vandetanib, 7.8 months with placebo) was longer than might have been expected in this third- and fourth-line treatment setting. In addition, the median duration of prior EGFR TKI therapy was approximately 5 months in both cohorts, suggesting that patients on this study had responded reasonably well to the previous EGFR TKI (both arms were similar in terms of the proportion of patients who had received gefitinib or erlotinib and the best response to these agents). These results may reflect the high proportion of patients with characteristics that have been previously shown as favorable for prognosis and/or response to EGFR TKIs, such as female sex, East Asian ethnicity, never smoker status, and adenocarcinoma histology.2,3,22–24 As such, the study population was not particularly representative of the general population of patients with pretreated advanced NSCLC. The relatively long duration of overall survival in the study might also reflect that more than 50% of patients in both arms received other anticancer therapy after discontinuation of randomized treatment, which is more than might have been expected in this refractory setting.
Although treatment with vandetanib did not confer an overall survival benefit, there were modest but statistically significant advantages favoring the vandetanib arm for the secondary end points of PFS and objective response rate. It is not clear why the PFS and overall survival outcomes were inconsistent. The two arms were well balanced at baseline, and the postprogression therapy seemed to be similar in both number and type. As discussed earlier, previous studies in patients with advanced NSCLC have suggested that certain factors may be predictive of benefit from EGFR TKIs.2,3,22,25 This is supported by the exploratory analyses performed in the present study, which indicated a differential PFS benefit for vandetanib in females, patients of East Asian origin, never smokers, adenocarcinoma histology, and a positive EGFR mutation status (although the limited availability of tumor biomarker data does not permit definitive conclusions). Patients previously treated with gefitinib also seemed to derive greater benefit from vandetanib than those who had received erlotinib. However, none of these subgroup advantages was seen for overall survival.
Because progressive disease is generally associated with deterioration in disease-related symptoms, it might also have been anticipated that the PFS advantage in vandetanib-treated patients would be accompanied by an improvement in time to worsening of disease-related symptoms. This association has previously been demonstrated for the addition of vandetanib to docetaxel in second-line NSCLC.14 However, there was no statistically significant difference between the vandetanib and placebo treatment arms for TDS in this study.
The safety profile was similar to that observed in other studies of vandetanib 300 mg monotherapy in previously treated advanced NSCLC.11,12 The most common adverse events in the vandetanib arm were consistent with pharmacodynamic inhibition of EGFR (skin reactions, diarrhea) and/or VEGFR signaling (hypertension). It is notable that the majority of patients were able to continue receiving study treatment without dose interruption or reduction or discontinuation of study treatment. The median duration of exposure to randomized treatment was similar across both patient cohorts; however, more patients in the vandetanib cohort experienced adverse events, including grade ≥ 3 adverse events, serious adverse events, and adverse events leading to discontinuation of study treatment.
In summary, this study did not demonstrate an improvement in the primary end point of overall survival with vandetanib versus placebo in patients with NSCLC after prior therapy with an EGFR tyrosine kinase inhibitor.
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: Laura Emerson, AstraZeneca (C); Peter Langmuir, AstraZeneca (C) Consultant or Advisory Role: Vera Hirsh, AstraZeneca (C); Keunchil Park, AstraZeneca (C) Stock Ownership: None Honoraria: Keunchil Park, AstraZeneca; Yuh-Min Chen, AstraZeneca, Roche; Christian Manegold, AstraZeneca, Eli Lilly, Roche, Merck Serono, Boehringer Inghelheim Research Funding: Jin Soo Lee, AstraZeneca Expert Testimony: None Other Remuneration: None
AUTHOR CONTRIBUTIONS
Conception and design: Jin Soo Lee, Peter Langmuir
Provision of study materials or patients: Jin Soo Lee, Vera Hirsh, Keunchil Park, Shukui Qin, Cesar R. Blajman, Reury-Perng Perng, Yuh-Min Chen, Christian Manegold
Collection and assembly of data: Laura Emerson, Peter Langmuir
Data analysis and interpretation: Jin Soo Lee, Vera Hirsh, Keunchil Park, Laura Emerson, Peter Langmuir
Manuscript writing: All authors
Final approval of manuscript: All authors
Acknowledgment
We thank the Independent Data Monitoring Committee (Malcolm Ranson, Philip Bonomi, Stuart Pocock, Tomohide Tamura, Pan-Chyr Yang) and the Independent Statistical Data Analysis Centre (Duolao Wang) for their valuable contribution to the oversight and conduct of this study.
Appendix
The following investigators also participated in the study: G. Lerzo, J.J. Zarba, S.A. Vigo, F. Rao, L. Fein, J.A. Perez (Argentina); G. van Hazel, N. Pavlakis, K. Pittman, K. Horwood, I. Burns (Australia); W. Pfeifer, R. Greil, N. Vetter (Austria); J. Van Meebeeck, J.-L. Canon, P. Germonpré, P. Collard, J. Vansteenkiste, L. Bosquée, F. Bustin, D. Galdermans (Belgium); S. Verma, M. Smylie, N. Leighl, R Wierzbicki (Canada); J. Fang, Y. Zhu, X. Liu, K. Nan, M. Wang, J. Chang, J. Feng, S. Yu, Y. Zhang, C. Zhou, Y. Wu, Y. Lu, Y. Cheng (China); P.-J. Souquet, R. Gervais, H. Berard, J. Otto, M. Perol, P. Rebattu, G. Robinet, A. Madroszyk (France); J. Mezger, J. Fischer, S. Gütz, J. von Pawel, W. Schütte, R. Bonnet, R.M. Huber, G. Hense, N. Dickgreber, H.-G. Derigs, H. Wirtz, S. Schüttrumpf (Germany); T. Mok, Y. Tung, D. Chua, S.-K. Au, A. Cheng (Hong Kong); A. Cyjon, M. Gottfried, A. Onn, N.P. Ramu (Israel); E. Bajetta, M. Tiseo, A. Martoni, A. Santoro, S. Siena, F. Grossi, G.V. Scagliotti, S. Cascinu, L. Crinò, H.J. Soto-Parra, F. De Marinis, G. Valmadre, G. Fasola (Italy); S.W. Kim, Jong-Seok Lee, J.H. Kim, S.H. Yang, J.H. Kang, H.-K. Kim, S.S. Won, J.-H. Choi (Korea); O. Arrieta, N. Barroso (Mexico); J.T. Bonte (the Netherlands); E. Amorín, H. Gomez, W. Rodriguez (Peru); R. Li, B. Tiangco, E.M. Villegas (the Philippines); A. Chang, R. Soo, T.E. Huat (Singapore); A. Blasco, A. Insa, O.J. Vidal, M.L. Brea, G.L. Vivanco, E. Felip, U. Jimenez (Spain); Y.-C. Sung, M.-L. Ho, M.-S. Huang, C.-T. Yang, J.W.-C. Chang, T.-C. Hsia, C.-J. Tsao, R.-K. Hsieh, K.-M. Rau, G.-C. Chang, H.-P. Kuo (Taiwan); S. Thongprasert, E. Sirachainan, A. Sookprasert, V. Sriuranpong, V. Srimuninnimit (Thailand); N. Davidson, M. Cullen, S. Beesley, E. Rankin, P. Taylor, F. Blackhall (United Kingdom); S. Katakkar, C.M. Jones, R. Rocha (United States).
Footnotes
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Supported by AstraZeneca (including medical writing support provided by John Matthew of Mudskipper Bioscience).
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Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Clinical trial information can be found for the following: NCT00404924.
- Received March 26, 2011.
- Accepted November 11, 2011.
