- © 2011 by American Society of Clinical Oncology
Vandetanib Plus Pemetrexed for the Second-Line Treatment of Advanced Non–Small-Cell Lung Cancer: A Randomized, Double-Blind Phase III Trial
- Richard H. de Boer,
- scar+Arrieta&sortspec=date&submit=Submit">Óscar Arrieta,
- Chih-Hsin Yang,
- Maya Gottfried,
- Valorie Chan,
- Johann Raats,
- Filippo de Marinis,
- Raymond P. Abratt,
- Jürgen Wolf,
- Fiona H. Blackhall,
- Peter Langmuir,
- Tsveta Milenkova,
- Jessica Read and
- Johan F. Vansteenkiste⇑
- From the Western Hospital, Melbourne, Australia; Instituto Nacional de Cancerología, Mexico City, Mexico; National Taiwan University Hospital, Taipei, Taiwan; Meir Medical Center, Kfar Saba, Israel; Veterans Memorial Medical Center, Quezon City, Philippines; Panorama Medical Center and New Groote Schuur Hospital, Cape Town, South Africa; San Camillo-Forlanini Hospital, Rome, Italy; Center for Integrated Oncology, University Hospital Cologne, Cologne, Germany; Christie Hospital National Health Service Foundation Trust, Manchester; AstraZeneca, Macclesfield, United Kingdom; AstraZeneca, Wilmington, DE; and University Hospital Leuven, Leuven, Belgium.
- Corresponding author: Johan F. Vansteenkiste, MD, PhD, Respiratory Oncology Unit, University Hospital Gasthuisberg, Herestraat 49, B-3000 Leuven, Belgium; e-mail: johan.vansteenkiste{at}uzleuven.be.
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Presented as a poster discussion at the 45th Annual Meeting of the American Society of Clinical Oncology, May 29-June 2, 2009, Orlando, FL, and as an oral presentation at the 13th World Congress on Lung Cancer, July 31-August 4, 2009, San Francisco, CA, and at the European Cancer Organisation 15/34th European Society for Medical Oncology Congress, September 20-24, 2009, Berlin, Germany.
Abstract
Purpose Vandetanib is a once-daily oral inhibitor of vascular endothelial growth factor receptor and epidermal growth factor receptor signaling. This randomized, placebo-controlled phase III study assessed the efficacy of vandetanib plus pemetrexed as second-line therapy in advanced non–small-cell lung cancer.
Patients and Methods Patients (N = 534) were randomly assigned to receive vandetanib 100 mg/d plus pemetrexed 500 mg/m2 every 21 days (n = 256) or placebo plus pemetrexed (n = 278). Progression-free survival (PFS) was the primary end point; overall survival, objective response rate, disease control rate, time to deterioration of symptoms, and safety were secondary assessments.
Results There was no significant difference in PFS between treatment arms (hazard ratio [HR], 0.86; 97.58% CI, 0.69 to 1.06; P = .108). Overall survival was also not significantly different (HR, 0.86; 97.54% CI, 0.65 to 1.13; P = .219). Statistically significant improvements in objective response rate (19% v 8%; P < .001) and time to deterioration of symptoms (HR, 0.71; P = .0052; median, 18.1 weeks for vandetanib and 12.1 weeks for placebo) were observed in patients receiving vandetanib. Adding vandetanib to pemetrexed increased the incidence of some adverse events, including rash, diarrhea, and hypertension, while showing a reduced incidence of nausea, vomiting, anemia, fatigue, and asthenia with no reduction in the dose intensity of pemetrexed.
Conclusion This study did not meet the primary end point of statistically significant PFS prolongation with vandetanib plus pemetrexed versus placebo plus pemetrexed. The vandetanib combination showed a significantly higher objective response rate and a significant delay in the time to worsening of lung cancer symptoms versus the placebo arm as well as an acceptable safety profile in this patient population.
INTRODUCTION
Conventional chemotherapy offers only a modest survival benefit to patients with advanced non–small-cell lung cancer (NSCLC). Vascular endothelial growth factor receptor (VEGFR) –dependent tumor angiogenesis and epidermal growth factor receptor (EGFR) –dependent tumor cell proliferation are clinically validated therapeutic targets in NSCLC.1–3 Moreover, EGFR is known to regulate the production of VEGF and other proangiogenic factors,4 and increased VEGF expression has been associated with resistance to EGFR inhibition in a human tumor xenograft model of NSCLC.5 Dual targeting of VEGFR and EGFR signaling in NSCLC is therefore a rational therapeutic approach.
Vandetanib (AstraZeneca, Macclesfield, United Kingdom) is a once-daily, oral anticancer agent that inhibits VEGFR-, EGFR-, and rearranged during transfection (RET) –dependent signaling.6,7 Phase I evaluation in patients with solid tumors demonstrated that vandetanib was generally well tolerated at ≤ 300 mg/d.8,9 A subsequent phase II program demonstrated the antitumor activity of vandetanib in patients with previously treated advanced NSCLC, both as monotherapy (300 mg/d)10 and in combination (100 mg/d) with docetaxel.11
Pemetrexed (Alimta; Eli Lilly, Indianapolis, IN) is a multitargeted antifolate chemotherapy agent approved for the treatment of advanced nonsquamous NSCLC.12–14 An open-label phase I study showed that vandetanib 100 mg/d was better tolerated than vandetanib 300 mg/d when given with pemetrexed in patients with previously treated advanced NSCLC.15 These phase I results and the improved efficacy with vandetanib 100 mg/d plus docetaxel in phase II11 supported further investigation of vandetanib 100 mg plus pemetrexed for second-line treatment of patients with advanced NSCLC in a randomized, double-blind, multicenter, placebo-controlled phase III study (Zactima Efficacy With Alimta in Lung Cancer [ZEAL]). The primary end point of the ZEAL study was progression-free survival (PFS); female patients were included as a coprimary analysis population on the basis of phase II data that suggested a more pronounced PFS benefit for vandetanib in combination with chemotherapy compared with chemotherapy alone in females.11,16
PATIENTS AND METHODS
Patients
Eligible patients were age ≥ 18 years who had histologically or cytologically confirmed locally advanced or metastatic (stage IIIB to IV) NSCLC after failure of first-line anticancer treatment, WHO performance status 0 to 2, life expectancy ≥ 12 weeks, and adequate hematologic, hepatic, renal, and cardiac function. Patients with squamous cell histology were permitted (recruitment was completed before labeling of pemetrexed for nonsquamous histology only) as were patients with pretreated clinically stable brain metastases. Exclusion criteria included chemotherapy or other anticancer therapy < 3 weeks before study entry, radiation therapy within 4 weeks before study entry, or prior treatment with pemetrexed or VEGFR tyrosine kinase inhibitors (TKIs). Prior treatment with bevacizumab or EGFR TKIs was permitted.
The study was conducted at 118 centers in 21 countries. All patients provided written informed consent, and 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.
Study Design and Treatments
Patients were randomly assigned 1:1 by a computer-generated scheme to receive once-daily oral vandetanib 100 mg plus pemetrexed (vandetanib arm) or oral placebo plus pemetrexed (placebo arm; Fig 1). Pemetrexed 500 mg/m2 was administered as an intravenous infusion every 21 days (maximum of six cycles). All patients received standard premedication for pemetrexed, including vitamin B12, folic acid, and dexamethasone. Patients continued blinded treatment with vandetanib or placebo until progressive disease, unacceptable toxicity, or withdrawal of consent. There was no crossover from placebo to vandetanib.
CONSORT diagram of patient disposition. Four patients were randomly assigned to placebo but inadvertently received at least one dose of vandetanib. In this figure, these patients are included in the placebo arm for the efficacy analysis but in the vandetanib arm for the safety analysis. ITT, intent-to-treat.
Study End Points
The primary objective was to demonstrate PFS prolongation in the vandetanib arm compared with the placebo arm. Secondary end points included overall survival (OS), objective response rate (ORR), disease control rate (DCR; complete response + partial response + stable disease ≥ 6 weeks), time to deterioration of symptoms (TDS), safety, and tolerability.
PFS was the interval from date of random assignment until date of objective progression or death (by any cause in the absence of progression), provided death was within 3 months from the last evaluable Response Evaluation Criteria in Solid Tumors (RECIST) v1.0 assessment. Patients underwent RECIST tumor assessments at baseline and every 6 weeks until disease progression or withdrawal of consent. Patients who had not progressed or had died at the time of analysis were censored at the time of their last tumor assessment. The final PFS analysis was to be conducted when 425 progression events had been observed.
Analysis of OS was conducted at the time of PFS analysis and was calculated from the date of random assignment to the date of death; patients who were alive at the time of analysis were censored at the time they were last known to be alive. An update of OS only was conducted in accordance with a request from the US Food and Drug Administration, and the results of this ad hoc analysis are reported in this article for completeness.
Symptoms were assessed by using the Lung Cancer Symptom Scale (LCSS) questionnaire17 at baseline and every 3 weeks thereafter until 30 days following progression (or discontinuation of vandetanib or placebo). TDS based on LCSS total score was defined as an increase from baseline of ≥ 10 mm on a scale from 0 to 100 with 0 representing the best score. A change of ≥ 10-mm was considered to be a clinically meaningful change in symptom severity as assessed by the LCSS.17,18 TDS was defined from the date of random assignment to the first assessment of deterioration with no improvement within the following 21 days. If deterioration was not observed at the time of analysis, TDS was censored at the time of the last complete LCSS assessment.
Adverse events were graded according to the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE) v3. ECGs were performed during screening, on day 1 (baseline), at 1, 3, 6, and 12 weeks after starting treatment, and then every 3 months up to and including discontinuation of vandetanib or placebo. The QTc interval was evaluated centrally, and prolongation was defined as described previously.19 Specific plans were in place for management of skin toxicity, GI toxicity, and QTc prolongation, as well as a general dose reduction scheme for any CTCAE grade 3 or 4 adverse event.
Statistical Methods
On the basis of earlier phase II results with vandetanib that suggested a more pronounced PFS benefit for vandetanib in combination with chemotherapy compared with chemotherapy alone in females,11,16 this study had two coprimary analysis populations: all randomly assigned patients (intent-to-treat) and all randomly assigned female patients. The study was designed to have 80% power to detect a 35% prolongation of PFS (hazard ratio [HR], < 0.74) at a two-sided significance level of 2.42% (the nominal two-sided significance level of 2.5% for a coprimary analysis was adjusted to allow for a single interim analysis). Assuming a median PFS of 3 months for pemetrexed,12 a total of 510 patients was estimated to achieve the required number of events with accrual over 12 months and a minimum follow-up of 6 months. PFS, OS, and TDS were analyzed by using a log-rank test. A secondary analysis of PFS and OS was performed by using a Cox proportional hazards regression model that included the effect of treatment, tumor stage, number of metastatic organs, previous bevacizumab, histology, smoking history, sex, and ethnic origin. ORR and DCR were analyzed by using logistic regression.
RESULTS
Patients
Between January 2007 and March 2008, 534 patients were assigned to the vandetanib arm (n = 256) or placebo arm (n = 278; Table 1). All patients were evaluable for efficacy; one patient randomly assigned to the placebo arm received no treatment and was excluded from the safety analysis. In addition, four patients randomly assigned to placebo who inadvertently received at least one dose of vandetanib were included in the vandetanib arm for the safety analysis (Fig 1). At data cutoff for the PFS analysis (September 5, 2008), 30 patients were still receiving treatment in the vandetanib arm versus 23 patients in the placebo arm; 181 patients entered the follow-up period for survival analysis (vandetanib, n = 90; placebo, n = 91).
Baseline Demographics and Patient Characteristics (intent-to-treat population)
Exposure
The median number of pemetrexed cycles was 5.0 (vandetanib arm) and 4.0 (placebo arm). Both arms had the same number of vandetanib or placebo dose interruptions or reductions (20%). The median duration of treatment was 102 days for the vandetanib arm and 85 days for the placebo arm.
Efficacy
PFS was analyzed after 443 progression events (vandetanib, n = 208; placebo, n = 235) and did not differ significantly between treatment arms (HR, 0.86; 97.58% CI, 0.69 to 1.06; P = .108; Fig 2); median PFS was 17.6 weeks for vandetanib and 11.9 weeks for placebo. At the time of PFS analysis, 269 patients had died: 122 (48%) in the vandetanib arm and 147 (53%) in the placebo arm. There was no significant difference in OS (HR, 0.86; 97.54% CI, 0.65 to 1.13; P = .219; Fig 2); median OS was 10.5 months for vandetanib and 9.2 months for placebo. The female coprimary analysis population results for PFS (HR, 0.86; 97.58% CI, 0.60 to 1.22; P = .319) and OS (HR, 0.91; 97.54% CI, 0.57 to 1.46; P = .662) were consistent with those for all patients. The effects of vandetanib plus pemetrexed on PFS and OS were consistent among the predefined clinical subgroups analyzed, with the possible exception of patients with squamous histology (Fig 3). Nonprotocol analyses of PFS and OS that included only patients with nonsquamous cell histology (vandetanib, n = 202; placebo, n = 218) showed improvements in both PFS (HR, 0.82; 97.58% CI, 0.64 to 1.04; P = .065; median PFS was 17.9 weeks for vandetanib and 11.9 weeks for placebo) and OS (HR, 0.81; 97.54% CI, 0.59 to 1.11; P = .129; median OS was 10.9 months for vandetanib and 9.5 months for placebo) for the vandetanib arm, but neither end point reached statistical significance. These additional analyses were conducted to accurately reflect the current prescribing information for pemetrexed that restricts use to patients with nonsquamous NSCLC. In the overall population, the vandetanib arm showed a statistically significant improvement in ORR (19% v 8%; P < .001) and DCR (57% v 46%; P = .0116).
Kaplan-Meier estimates of (A) progression-free survival (PFS) and (B) overall survival in the intent-to-treat population (all patients). HR, hazard ratio.
Hazard ratios (HRs) for (A) progression-free survival and (B) overall survival by baseline clinical characteristics in intent-to-treat population (all patients). HR < 1 favors the vandetanib arm.
At the time of the survival follow-up analysis (September 1, 2009), 389 patients had died: 181 (71%) in the vandetanib arm and 208 (75%) in the placebo arm. There was no significant difference in OS between the treatment arms (HR, 0.89; 95% CI, 0.73 to 1.09; P = .269); median OS was 9.8 months for vandetanib and 9.2 months for placebo. The predefined subgroup results for OS were consistent with those from the primary analyses of PFS and OS (Fig 3).
Time to Deterioration of Symptoms
Overall patient compliance with the LCSS questionnaire (defined as patients with a baseline assessment and at least one postbaseline assessment) was 82% for vandetanib and 86% for placebo. There was a statistically significant prolongation in TDS, as measured by LCSS total score, for patients in the vandetanib arm versus the placebo arm (HR, 0.71; 97.5% CI, 0.54 to 0.94; P = .0052; Fig 4).
Kaplan-Meier estimates of time to deterioration of symptoms according to Lung Cancer Symptom Scale total score in the intent-to-treat population (all patients). PFS, progression-free survival; HR, hazard ratio.
Safety and Tolerability
Across both arms, common adverse events were fatigue, nausea, rash, and cough (Table 2). Adverse events (all grades) typically associated with inhibitors of VEGFR or EGFR signaling were more frequent in the vandetanib arm, including rash (38% v 26%), diarrhea (26% v 18%), and hypertension (12% v 3%). Adverse events with a lesser frequency in the vandetanib arm were anemia (8% v 22%), fatigue (39% v 45%), asthenia (11% v 17%), nausea (29% v 37%), and vomiting (15% v 22%).
Common Adverse Events Reported in ≥ 20% of Patients in Either Treatment Arm (safety population)
Combining vandetanib and pemetrexed did not produce substantial additional toxicity versus pemetrexed alone. The incidence of CTCAE grade ≥ 3 events was similar across both arms (vandetanib, 52%; placebo, 49%); notable differences included a higher incidence of grade ≥ 3 rash (6% v 3%) and diarrhea (4% v 2%) with vandetanib, whereas grade ≥ 3 anemia was more frequent in the placebo arm (1% v 6%). The incidence of serious adverse events was similar (32% v 34%). There was a modest increase in the number of patients discontinuing andetanib because of adverse events compared with those receiving placebo (16% v 11%), mainly due to rash (3% v 0%).
Elevated blood pressure (> 160 mmHg systolic; > 100 mmHg or change from baseline > 20 mmHg diastolic) was more common in the vandetanib arm (29% v 13%). Most hypertension adverse events were grade 1 to 2, with grade 3 to 4 events reported in 2% of the patients in the vandetanib arm and in 1% in the placebo arm. One patient in the vandetanib arm experienced protocol-defined QTc prolongation, which was asymptomatic and resolved without dose interruption or reduction.
No clinically significant changes in renal function were observed with either treatment, and most changes in liver function were manageable with the exception of two patients receiving vandetanib who experienced CTCAE grade 3 elevated liver enzymes and discontinued vandetanib. Fewer patients in the vandetanib arm received erythropoietin (2% v 11%), blood transfusions (5% v 11%), or oral iron supplementation (3% v 6%).
The incidence of hemorrhagic events (hemoptysis, epistaxis, gi bleeding, hematuria, metrorrhagia, or CNS hemorrhage) was similar in both treatment arms. hemoptysis was reported in 14 patients (5%) in the vandetanib arm and 19 patients (7%) in the placebo arm; two cases of fatal hemoptysis were reported in each arm. One patient in each arm had nonfatal cerebral hemorrhage, neither of whom had known brain metastases. One patient on each arm died as a result of pulmonary embolism. interstitial lung disease-like events occurred in seven patients (vandetanib, n = 3; placebo, n = 4), none of which were fatal.
Most deaths during treatment or during the 60-day safety follow-up were due to NSCLC (247 [92%] of 269;). Serious adverse events reported as leading to death occurred in 14 patients (5%) in the vandetanib arm and 12 patients (4%) in the placebo arm. Irrespective of causality, the most common adverse events reported as leading to death were respiratory failure, pneumonia, and hemoptysis, which are consistent with the natural history for patients with lung cancer.
DISCUSSION
None of the currently approved single-agent second-line therapies, including docetaxel, pemetrexed, gefitinib, and erlotinib,2,3,12,20,21 have shown superior efficacy to any other in unselected populations, and combination chemotherapy has failed to show consistent benefits over single-agent regimens.22–25 Thus, there is an unmet need for second-line treatments that are tolerable, improve efficacy, and alleviate symptom burden.
This randomized phase III study evaluated vandetanib in combination with pemetrexed versus pemetrexed alone, but it did not meet its primary end point of statistically significant PFS prolongation with the addition of vandetanib. PFS was selected as the primary end point to provide a direct measurement of the effect of study treatment on the tumor not potentially confounded by the use of postprogression therapies.26 Approximately 50% of patients received some form of subsequent cancer therapy in this study. The numbers and types of cancer therapies were balanced across arms, but differences in response to postprogression therapy between treatment groups may have influenced the OS outcome.
Statistically significant advantages favoring the vandetanib combination were observed for ORR and DCR, the ORR being more than twice that observed with pemetrexed alone (19% v 8%). In addition, a significant delay in the time to deterioration of common lung cancer symptoms (as measured by LCSS total score) was observed. Progressive disease is generally associated with a deterioration in disease-related symptoms and health-related quality of life,27 and the results of this study suggest that the slowing of disease progression may be associated with improved symptom relief.
Certain baseline clinical factors of patients with advanced NSCLC have been suggested as predictors of sensitivity to agents targeting EGFR2,28,29 or VEGF signaling.1 Predefined subgroup analyses of patient and clinical characteristics showed no clear evidence of significant differential benefit for PFS or OS. It is noteworthy that recruitment to the Zactima Efficacy with Alimta in Lung Cancer (ZEAL) trial was completed before the pemetrexed prescribing information was revised (April 2008) to restrict pemetrexed use to patients with nonsquamous NSCLC. Nonprotocol analyses of PFS and OS in patients with nonsquamous cell histology demonstrated modest reductions in hazard ratios for each end point compared with those for the overall population. However, consistent with the per-protocol analysis, these results did not reach statistical significance for either end point.
Vandetanib 100 mg/d in combination with pemetrexed was tolerable, with an adverse event profile generally consistent with those of previous studies of vandetanib and/or pemetrexed in NSCLC.11,12,15 rash, diarrhea, and hypertension were more frequently observed in the vandetanib arm, and these events are consistent with inhibition of VEGFR (hypertension)30 or EGFR (diarrhea, rash).31 Importantly, combination treatment did not produce substantial additional toxicity compared with pemetrexed alone, including no increase in hemorrhagic or thromboembolic events or in interstitial lung disease-like events. Vandetanib did not appear to compromise the dosing of pemetrexed, with a higher median number of pemetrexed cycles (5 v 4). Interestingly, the vandetanib arm showed a reduced incidence of some adverse events (anemia, fatigue, asthenia, nausea, and vomiting) commonly associated with chemotherapy treatment. The reduced incidence of anemia in patients treated with vandetanib may be due to inhibition of VEGF signaling, which has been reported to enhance erythropoiesis in preclinical models.32 The lower incidence of nausea and vomiting with vandetanib did not appear to be due to an increased use of antiemetics. A similar pattern of reduced nausea, vomiting, and anemia was observed in the vandetanib arm of the Zactima in Combination With Docetaxel in Non–Small-Cell Lung Cancer (ZODIAC) phase III study (vandetanib plus docetaxel v docetaxel in previously treated NSCLC).33
The ZEAL study design was analogous to that of the larger ZODIAC study,33 and the results of the two studies were generally consistent. The ZODIAC study demonstrated significant prolongation of PFS with vandetanib plus docetaxel versus docetaxel alone. Both studies showed that adding vandetanib significantly improved ORR and delayed the time to worsening of lung cancer symptoms. Although these results indicate that targeting VEGFR and EGFR with vandetanib has antitumor activity when combined with pemetrexed or docetaxel, this did not translate into a clinical benefit in terms of PFS or OS. Previous studies of selective EGFR TKIs have shown no additional clinical benefit when added to chemotherapy in first-line NSCLC,34–37 and a role for VEGFR TKIs in the treatment of NSCLC remains to be established. One can speculate whether improved results could be obtained by a more selective targeting of patients with specific biomarkers predictive of drug sensitivity. Unfortunately, such biomarkers remain to be identified for anti-VEGF agents, and apart from EGFR mutations, remain uncertain for anti-EGFR agents. Ideally, predictive markers should be identified in advance of phase III trials. In this context, vandetanib showed significant advantages for two subgroups (females and patients with low baseline VEGF) during phase II evaluation in NSCLC,11,16,38 but these findings were not reproduced in the phase III setting.
In conclusion, this randomized phase III study did not meet its primary end point of statistically significant PFS prolongation for vandetanib plus pemetrexed versus pemetrexed alone in patients with pretreated advanced NSCLC.
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: Peter Langmuir, AstraZeneca(C); Tsveta Milenkova, AstraZeneca (C); Jessica Read, AstraZeneca (C) Consultant or Advisory Role: Richard H. de Boer, AstraZeneca (C);Chih-Hsin Yang, AstraZeneca (C); Jürgen Wolf, AstraZeneca (C); Johan F. Vansteenkiste, AstraZeneca (C) Stock Ownership: Tsveta Milenkova, AstraZeneca Honoraria: Richard H. de Boer, AstraZeneca; Chih-Hsin Yang, AstraZeneca; Jürgen Wolf, AstraZeneca Research Funding: Richard H. de Boer, AstraZeneca; Valorie Chan, AstraZeneca, Roche, GlaxoSmithKline; Fiona H. Blackhall, AstraZeneca Expert Testimony: None Other Remuneration: Fiona H. Blackhall, Lilly Oncology
AUTHOR CONTRIBUTIONS
Conception and design: Richard H. de Boer, Peter Langmuir, Tsveta Milenkova, Johan F. Vansteenkiste
Provision of study materials or patients: Richard H. de Boer, Óscar Arrieta, Chih-Hsin Yang, Maya Gottfried, Valorie Chan, Johann Raats, Filippo de Marinis, Raymond P. Abratt, Jürgen Wolf, Fiona H. Blackhall, Johan F. Vansteenkiste
Collection and assembly of data: Richard H. de Boer, Óscar Arrieta, Chih-Hsin Yang, Maya Gottfried, Johann Raats, Raymond P. Abratt, Jürgen Wolf, Tsveta Milenkova, Johan F. Vansteenkiste
Data analysis and interpretation: Richard H. de Boer, Peter Langmuir, Tsveta Milenkova, Jessica Read, Johan F. Vansteenkiste
Manuscript writing: Richard H. de Boer, Óscar Arrieta, Chih-Hsin Yang, Maya Gottfried, Valorie Chan, Johann Raats, Filippo de Marinis, Raymond P. Abratt, Jürgen Wolf, Fiona H. Blackhall, Peter Langmuir, Tsveta Milenkova, Jessica Read, Johan F. Vansteenkiste
Final approval of manuscript: Richard H. de Boer, Óscar Arrieta, Chih-Hsin Yang, Maya Gottfried, Valorie Chan, Johann Raats, Filippo de Marinis, Raymond P. Abratt, Jürgen Wolf, Fiona H. Blackhall, Peter Langmuir, Tsveta Milenkova, Jessica Read, Johan F. Vansteenkiste
Acknowledgment
We thank Malcolm Ranson, Philip Bonomi, Stuart Pocock, Tomohide Tamura, and Pan-Chyr Yang of the Independent Data Monitoring Committee along with Duolao Wang of the Independent Statistical Data Analysis Centre for their valuable contribution to the oversight and conduct of this study. We also thank Chris Watson of Mudskipper Bioscience for editorial assistance.
Appendix
The following individuals were also investigators in this study: W. Ackerley, T. Almodovar, S. Ariad, D. Bafaloukos, C.I. Bagnes, E. Bajetta, L. Beckman, P. Bergstrom, C. Biran, C.R. Blajman, J.L. Bogacz, P. Buchunow, W.I. Burns, F. Bustin, A. Canhola, R.T. Chacko, M. Cobo, G. Cohen (South Africa), G. Cohen (USA), R. Corcho, G. Cornelio, L. Crino, A. Cyjon, M. De La Colina, C. Desai, N.J. Dickgreber, L.E. Ek, M.A. Escudero, S.V. Estevez, E. Fabre-Guillevin, J.D. Fain, D. Ferry, R.G. Fisher, G. Fountzilas, G. Fraboulet, M.A. Gancedo, M. Gips, S. Glutz, F. Grossi, A. Guerrero, P. Hesketh, W. Hilgers, D. Hill, J.C.M. Ho, B. Hughes, Y. Humblet, A.P. Huñis, R.C. Inhorn, J. Jordaan, H. Kalafonos, A. Kallab, R. Kerr, K. Lamberg-Lundström, C.R. Lewis, P. Lianes, K. Maart, R.M. Mall, N. Marrero, L.A.L. Mateos, A. Meleiro, J. Merzger, I. Oliff, E. Paschold, N. Pavlakis, J.L.F. Perez, M. Perol, D. Perry, N. Peylan-Ramu, F. Pimentel, A.I. Pirjol, S. Poli, A. Price, M. Provencio, M.E.L. Quintela, E. Quoix, G. Rojas, R. Santos, G. Scagliotti, J. Schneider, M. Shtivelband, S. Siena, H. Singh, M. Snee, L. Steinholtz, A. Sulkes, S. Tannenbaum, G. Thomas, J. Thompson, J. Tseng, D. Tudtud, C. Umbria, C. Underhill, M. Uy, C. Vargas, S.A. Vigo, A. Villalon, N. Vrindavanam, R.C. Wainstein, J. Wallmark, D. Waterhouse, P. Weinstein, S. White, M. Wolf, M. Wollner, M.A. Zaydan, and J. Zidan.
Footnotes
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See accompanying article on page 1059
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Supported by AstraZeneca.
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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: NCT00418886.
- Received March 29, 2010.
- Accepted September 13, 2010.
