- © 2008 by American Society of Clinical Oncology
Lapatinib Versus Hormone Therapy in Patients With Advanced Renal Cell Carcinoma: A Randomized Phase III Clinical Trial
- Alain Ravaud,
- Robert Hawkins,
- Jason P. Gardner,
- Hans von der Maase,
- Niko Zantl,
- Peter Harper,
- Frédéric Rolland,
- Bruno Audhuy,
- Jean-Pascal Machiels,
- Frank Pétavy,
- Martin Gore,
- Patrick Schöffski and
- Iman El-Hariry
- From the Department of Medical Oncology, Hôpital Saint André, Bordeaux; Department of Medical Oncology, Centre René Gauducheau, St Herblain; Department of Medical Oncology, Hôpital Pasteur, Colmar, France; Department of Medical Oncology, Christie Hospital, Manchester; GlaxoSmithKline, Greenford; Department of Medical Oncology, Guys and St Thomas's Hospitals; Department of Medical Oncology, Royal Marsden Hospital, London, United Kingdom; Department of Medical Oncology, Rigshospital, Copenhagen, Denmark; Department of Medical Oncology, Technische Universität München, München, Germany; Department of Medical Oncology, Université Catholique de Louvain, Brussels; and Department of Medical Oncology, Universitair Zeikenhuis Gasthuisberg, Leuven, Belgium
- Corresponding author: Alain Ravaud, MD, PhD, Department of Medical Oncology, Hôpital Saint André, CHU Bordeaux, 1 rue Jean Burguet, 33075 Bordeaux cedex, France; e-mail: alain.ravaud{at}chu-bordeaux.fr
Abstract
Purpose Lapatinib is an orally reversible inhibitor of epidermal growth factor receptor (EGFR)/human epidermal growth factor receptor 2 (HER-2) tyrosine kinases with demonstrated activity in patients with HER-2–positive breast cancer. In the current phase III open-label trial, lapatinib was compared with hormone therapy (HT) in patients with advanced renal cell carcinoma (RCC) that express EGFR and/or HER-2.
Patients and Methods Patients with advanced RCC who had experienced disease progression through first-line cytokine therapy—stratified by Karnofsky performance status and number of metastatic sites—were randomly assigned to lapatinib 1,250 mg daily or HT. The primary end point was time to progression (TTP); secondary end points included overall survival (OS), safety, and biomarker analyses.
Results Four hundred sixteen patients were enrolled onto the study. Median TTP was 15.3 weeks for lapatinib versus 15.4 weeks for HT (hazard ratio [HR] = 0.94; P = .60), and median OS was 46.9 weeks for lapatinib versus 43.1 weeks for HT (HR = 0.88; P = .29). In a biomarker analysis of patients with EGFR-overexpressed tumors (3+ by immunohistochemistry [IHC]; n = 241) median TTP was 15.1 weeks for lapatinib versus 10.9 weeks for HT (HR = 0.76; P = .06), and median OS was 46.0 weeks for lapatinib versus 37.9 weeks for HT (HR = 0.69; P = .02). These results were confirmed by Cox regression analysis. No unexpected toxicities were observed; the most commonly reported drug-related adverse events (all grades) for lapatinib were rash (44%) and diarrhea (40%).
Conclusion Lapatinib was well tolerated with equivalent overall efficacy to HT in advanced RCC patients who had experienced disease progression while receiving cytokines, and the study supports that lapatinib prolonged OS relative to HT in patients with 3+ EGFR status determined by IHC.
INTRODUCTION
The incidence of renal cell carcinoma (RCC) is increasing in Europe and the United States.1 Metastatic RCC is insensitive to chemotherapy and shows low rates of response to immunotherapy.2 However, antiangiogenic-targeted therapies such as sunitinib and sorafenib have emerged as important new standard treatments in first-line treatment or after failure of immunotherapy.3,4
Epidermal growth factor receptor (EGFR) and its ligands, EGF and transforming growth factor α (TGF-α), are overexpressed in RCC.5,6 Both ligands stimulate the proliferation of human RCC cell lines, while inhibitors of EGFR inhibit proliferation and tumor growth in vitro and in vivo.5,6 In addition, EGFR signaling is involved in the tumorigenesis associated with mutations of the von Hippel-Lindau (VHL) tumor suppressor gene, which are found in the majority of cases of clear cell RCC.7,8 The role of the related receptor, human epidermal growth factor receptor 2 (HER-2, or ErbB2), in RCC pathogenesis is less clear; however, co-overexpression of EGFR and HER-2 is associated with metastatic disease.9 Lapatinib (Tykerb/Tyverb; GlaxoSmithKline, Research Triangle Park, NC) is a dual inhibitor of the intracellular tyrosine kinase domains of EGFR and HER-2, and has recently demonstrated efficacy in a randomized phase III study in combination with chemotherapy in HER-2–overexpressing breast cancer patients.10 Lapatinib is a particularly attractive agent to study in advanced RCC.
Therefore, we conducted a prospective, open-label, randomized phase III trial of lapatinib in patients with advanced RCC that expressed EGFR or HER-2, and had experienced disease progression while receiving first-line cytokine therapy. At the time this trial was designed, there were limited treatment options for RCC patients who had experienced disease progression while receiving cytokine therapy. Hormone therapy (HT) was selected for the control arm in the trial because it is well tolerated and was used as a standard comparison treatment in a seminal randomized trial.11
PATIENTS AND METHODS
Patients
Eligible patients had histologically or cytologically confirmed, locally advanced or metastatic RCC of any histologic subtype that was not amenable to curative surgery or radiotherapy. Other inclusion criteria included disease progression after or intolerance to first-line cytokine-based therapy; expression of EGFR and/or HER-2 in tumor tissue with immunohistochemistry (IHC) 1+, 2+, or 3+; measurable disease according to the Response Evaluation Criteria in Solid Tumors; cardiac ejection fraction within institutional normal limits as measured by multigated acquisition scan or echocardiography; age ≥ 18 years; Karnofsky performance status (KPS) ≥ 70%; and life expectancy ≥ 12 weeks. Prior systemic neoadjuvant or adjuvant therapy was allowed. Patients had to have adequate hematologic, renal, and hepatic function, defined as granulocyte count ≥ 1,500/μL; platelet count ≥75,000/μL; hemoglobin ≥ 9 g/dL; serum creatinine ≤ 180 μmol/L and estimated creatinine clearance ≥ 30 mL/min; total bilirubin less than 1.5× the upper limit of normal (ULN); ALT less than 3× ULN unless due to disease, in which case up to 5× ULN was allowed. Exclusion criteria included prior or concurrent treatment with an EGFR or HER-2 inhibitor; concurrent systemic corticosteroid therapy; recently completed or concurrent treatment with another investigational therapy; active CNS metastases; malabsorption syndrome or other GI disease or resection that could affect absorption; and severe cardiovascular disease or cardiac disease requiring a device. The study was approved by the institutional review board or independent ethics committee at each clinical site. All patients gave written informed consent before participating in the trial.
Study Design
Patients were randomly assigned to receive lapatinib 1,250 mg daily or HT. Randomization was done centrally via an interactive voice response system, and stratified according to KPS (70% to 80%, or 90% to 100%) and the number of metastatic sites (≤ two or > two).
Lapatinib was administered the same time each day immediately after the morning meal; HT was also administered daily, and consisted of megestrol acetate or tamoxifen selected and provided by the investigator. All patients were treated until disease progression or withdrawal from the study, and were evaluated for toxicity every 4 weeks. Those patients who had derived clinical benefit as determined by the investigator were allowed to continue receiving treatment even after evidence of radiologic disease progression.
The study was designed in 2001, initially as a phase II randomized trial using objective response rate as the primary end point. In 2002, emerging evidence demonstrated that time to disease progression was a more suitable end point for targeted therapies than response rate, and the design was modified to incorporate time to progression (TTP) as a new primary end point.12,13 A total of 110 patients were recruited after completing the phase II part of the study. The study accrual was stopped for 3 months in the interim until the protocol was amended and local ethics committee approvals were obtained. The study was also expanded to a phase III design based on results from a preplanned interim analysis of safety data alone. Throughout the amendment, the investigators and the sponsor were blinded to the results.
The primary end point was TTP, defined as the interval between date of randomization and the earliest date of radiologically confirmed progression by independent review or death due to RCC, in the intent-to-treat population. Secondary end points included tumor response rate; time to response; clinical benefit; overall survival (OS); and correlative analysis of tumor biomarkers, including analysis of TTP and OS, depending on level of expression of EGFR and/or HER-2.
Further determination of efficacy was based on objective measurements of disease using Response Evaluation Criteria in Solid Tumors.14 Disease assessment was done at baseline, then every 8 weeks after initiating treatment. Patients experiencing a partial response (PR) or complete response had to have a confirmatory assessment at least 4 weeks later. Disease assessments were continued until progressive disease was documented, even if treatment was discontinued. All scans were reviewed by a blinded, independent radiologic review board (Synarc, San Francisco, CA).
Safety was assessed by analyzing the physical examination findings, CBCs, coagulation parameters, clinical chemistry, urinalysis, and KPS (assessed every 4 weeks); 12-lead ECG, conducted at baseline and follow-up; multigated acquisition scan or echocardiography (conducted every 8 weeks); and adverse events. All randomly assigned patients who received at least one dose of the study drug were included in the safety population. Adverse events were rated by the investigators using the National Cancer Institute Common Toxicity Criteria v2.0.15
IHC for EGFR (PharmDx; Dako, Glostrup, Denmark) and HER-2 (HercepTest, Dako) expression was performed centrally in a blinded, independent manner by Quest Diagnostics (Madison, NJ) using fresh or paraffin-embedded biopsy tissue taken from primary and/or metastatic tumor sites before the patient was enrolled onto the study. Moderate to strong complete membrane staining in more than 10% of the tumor cells was classified as 3+ strongly positive.
Statistical Analysis
It was determined that a total of 257 TTP events would be required to detect a 50% increase in the median TTP (from 4 to 6 months) between groups using a log-rank test at the two-sided 5% significance level with 90% power. To allow for losses to follow-up of up to 10% of patients, it was determined that 400 patients would need to be enrolled. Interim analyses for safety and futility were dictated by the protocol after 100 and an additional 100 patients (total of 200 patients) were enrolled and observed for at least 16 weeks. An independent data-monitoring committee evaluated the interim data to provide an opportunity to terminate the study if concerns about safety arose or if there was adequate evidence to reject the alternative hypothesis that lapatinib improves TTP by 50% compared with hormonal treatment in favor of the null hypothesis.
TTP was summarized using inverse cumulative incidence curves, from which median TTP was calculated. Treatment arms were compared using the stratified log-rank test, and an estimate of the hazard ratio (HR) and corresponding 95% CI were calculated. Tumor response rates and clinical benefit (overall response rate [complete response + PR] + stable disease at 6 months) rates in each group were compared using stratified Fisher's exact tests, with 95% CI calculated for differences in rates between groups.
A Cox regression analysis for OS was performed on the following subgroups: treatment with lapatinib versus HT and EGFR (0, 1+, or 2+ v 3+). The regression model was adjusted for KPS and number of metastatic sites. A risk factor analysis was also conducted according to key categoric variables relevant in this patient population: KPS (< 80% or ≥ 80%), hemoglobin (less than normal or more than normal), corrected serum calcium (≤ 10 or > 10 mg/dL) to define risk groups.16
RESULTS
Patients
Between December 2002 and February 2005, a total of 416 patients from 116 centers in 11 countries were randomly assigned to receive lapatinib (n = 209) or HT (n = 207). Figure 1 shows the patients’ progression through the trial, and Table 1 lists the baseline characteristics of the enrolled patients. The two treatment arms were well balanced for all baseline factors, including EGFR expression levels and the relevant prognostic risk factors in this patient population.16 The majority of patients had clear cell histology (87%) and high (IHC 3+) tumor expression of EGFR (58%).
Trial profile. HT, hormone therapy; ITT, intent to treat.
Baseline Patient Characteristics of the 416 Patients Included in the Analysis
Efficacy
The planned analysis of efficacy end points, including EGFR expression, was performed when 257 progression events by independent assessment were achieved in September 2005, and the results are presented here. For time-to-event end points, the last date of known contact was used for those patients that had not reached the event at the time of analysis, and such patients were considered as censored in the analysis.
Median TTP, the primary end point, was similar between treatment arms in the intent-to-treat analysis (Fig 2A). The median TTP was 15.3 weeks in the lapatinib arm versus 15.4 weeks in the HT arm (HR, 0.94; P = .595; 95% CI, 0.75 to 1.18). Median OS (Fig 2B), was 46.9 weeks in the lapatinib arm and 43.1 weeks in the HT arm (HR, 0.88; P = .290; 95% CI, 0.69 to 1.12).
Kaplan-Meier estimates of cumulative incidence of time to progression (TTP) according to the assessment of the independent review committee (A, C, E) and overall survival (OS; B, D, F). (A) TTP in the intent-to-treat (ITT) population for lapatinib versus hormone therapy (HT). (B) OS in the ITT population for lapatinib versus HT. (C) TTP for lapatinib versus HT in patients with tumor epidermal growth factor receptor (EGFR) 0, 1, 2+ intensity staining. (D) OS for lapatinib versus HT in patients with tumor EGFR 0, 1, 2+ intensity staining. (E) TTP for lapatinib versus HT in patients with tumor EGFR 3+ intensity staining. (F) OS for lapatinib versus HT in patients with tumor EGFR 3+ intensity staining. HR, hazard ratio.
Tumor response rate (PR only) was 1.4% and 0.5% in the lapatinib and HT groups, respectively. Approximately one third of patients in each arm experienced stable disease at 2 months as the best response to treatment (66 [32%] in the lapatinib arm, and 65 [31%] in the HT arm). Rates of clinical benefit (PR or stable disease ≥ 6 months) were similar between arms: 8.1% with lapatinib and 9.7% with HT.
Exploratory analyses of TTP and OS were conducted based on EGFR tumor expression levels as part of the secondary biomarker end point. Significant differences were not observed between groups for TTP or OS for patients with EGFR 0, 1+, or 2+ staining intensity (Figs 2C and 2D). In the group of patients with EGFR 3+ tumors, median TTP was prolonged over 4 weeks in the lapatinib arm (HR, 0.76; 95% CI, 0.6 to 1.0; P = .06) from 10.9 to 15.1 weeks, and median OS was significantly increased by more than 8 weeks (HR, 0.69; 95% CI, 0.5 to 1.0; P = .019) from 37.9 to 46.0 weeks (Figs 2E and 2F). These results were confirmed by multivariate Cox regression modeling, which demonstrated no treatment difference in the patients with low expression of EGFR (HR, 1.18; 95% CI, 0.80 to 1.73; P = .40), and a significant effect on OS between the two treatment groups for patients with EGFR 3+ expression (HR, 0.66; 95% CI, 0.48 to 0.91; P = .012).
After progression, approximately half of the patients in each arm (92 receiving lapatinib and 105 receiving HT) received subsequent therapy. Those patients who had derived clinical benefit continued to receive treatment as determined by the investigator after disease progression. These included 49 patients in the lapatinib arm (average duration 25 days), and 45 patients in the HT arm (average duration 28 days). Other therapies included antiangiogenesis agents, and were evenly distributed between the arms (13 after lapatinib v 15 after HT).
Safety
Table 2 summarizes the most commonly reported drug-related adverse events in the safety population. In the lapatinib arm, these events were rash (44%), diarrhea (40%), and nausea (18%). The majority of drug-related adverse events were grade 1 and 2, and the overall incidence of grade 3 and 4 events was low (7.3% with lapatinib [n = 15] and 2.0% with HT [n = 3]). No grade 4 events were reported in the lapatinib arm. Adverse events led to treatment discontinuation in 13% (n = 26) and 9% (n = 18) of patients in the lapatinib and HT arms, respectively. Two patients in the lapatinib group died as a result of a serious, drug-related adverse event. One of these patients developed a fatal cerebral hemorrhage 265 days after starting lapatinib. The other patient developed interstitial pulmonary fibrosis after completing lapatinib treatment 201 days earlier, and this event was categorized by the investigator as drug related.
Drug-Related Adverse Events in the Patients Included in the Safety Population
DISCUSSION
This large, phase III trial of lapatinib versus HT did not meet the primary end point in the overall population of advanced RCC patients whose disease had previously progressed after cytokine-based therapy. However, based on an exploratory analysis of EGFR level expression in tumors, treatment with lapatinib seemed to prolong survival relative to HT in patients with high levels of tumor EGFR.
EGFR is a well-described potential therapeutic target in RCC. Both EGFR and its ligand TGF-α are overexpressed in RCC, and TGF-α is a critical mitogen for the autonomous growth of VHL-inactivated (VHL−/−) RCC cells.8 Indeed, the TGF-α/EGFR pathway seems to be an important pathway for carcinogenesis in VHL−/− RCC. When EGFR is inhibited, the autonomous growth of VHL−/− RCC cells is abolished in vitro.8 As such, several EGFR inhibitors have been evaluated in phase II trials in RCC. The anti-EGFR monoclonal antibody (mAb), cetuximab, produced no responses among 55 patients with metastatic RCC treated in a single-arm phase II trial,17 whereas a similar anti-EGFR mAb, panitumumab, produced three major responses, two minor responses, and disease stabilization in 44 patients with metastatic RCC treated in a dose-ranging trial (N = 88).18 The small-molecule tyrosine kinase inhibitors, gefitinib and erlotinib, have not demonstrated significant activity with respect to response rates in phase II trials, although disease stabilization was reported in approximately 25% to 50% of patients.19-22 Dual targeted therapy with a combination of erlotinib and bevacizumab, a mAb directed against vascular endothelial growth factor, seemed to have promising activity in metastatic RCC in a single-arm, open-label trial.23 However, the combination was not found to be superior to bevacizumab alone in this setting.24 None of these studies with EGFR inhibitors selected patients for target expression or analyzed the results based on EGFR levels.
To our knowledge, this was the first randomized phase III trial of an EGFR/HER-2 inhibitor in RCC patients who were selected for expression of either target receptor. EGFR was overexpressed (IHC 3+) by the majority (58%) of patients; conversely, HER-2 was detected in only 5% of patients. The exploratory subset analysis in the EGFR-overexpressing patients (n = 241) was conducted as part of the biomarker secondary end point of this study to generate hypotheses and showed that OS was more prolonged in the lapatinib arm than in the HT arm (HR = 0.69). Two nonexclusive hypotheses could explain the results observed in the current study. First, EGFR is a poor prognostic factor in several malignancies, and is associated with reduction in survival. Previous smaller studies in RCC have suggested that the presence and/or expression level of EGFR could have a deleterious impact on survival.5,25 Therefore, patients in the control arm with high EGFR-expressing tumors may have significantly worse prognosis than patients with tumors expressing reduced EGFR. These observations were confirmed in the current study, where patients overexpressing EGFR in the control arm had a poorer outcome than those with low levels of tumor EGFR expression (37.9 v 54.1 weeks; P < .01). Second, lapatinib is an active inhibitor of tumor EGFR in vivo and is most efficacious in patients who express higher levels of EGFR (IHC 3+) than lower levels (IHC 0, 1+, or 2+) when compared with the control arm. This rationale is consistent with previous studies of targeted agents, including lapatinib, which have demonstrated efficacy in patients who overexpressed HER-2.10
Lapatinib is a dual-targeted inhibitor of EGFR and HER-2, and potently blocks the intense signaling via the EGFR/HER-2 heterodimer pathway that has been shown to induce tumor cell proliferation. Therefore, a complementary hypothesis is that more complete inhibition that translates to clinical benefit may be possible in RCC when EGFR expression is upregulated, even though HER-2 expression is low. Additional biomarker studies are underway to investigate these hypotheses and other potential pathways.
HT offers only symptomatic benefit to RCC patients with a well-tolerated safety profile, and is widely administered to patients who have experienced disease progression while receiving standard first-line therapy.11 Furthermore, expression of hormone receptors was detected in only 1% of RCC patients26; therefore, the use of HT in the current trial would not be expected to influence the efficacy results in the EGFR subpopulations.
Although patients were not stratified for the established risk factors in the second-line RCC setting,16 a retrospective analysis demonstrated that the distributions of KPS, corrected serum calcium, and hemoglobin were well balanced between the two treatment arms and in each of the EGFR subgroups. Moreover, the use of subsequent therapies after progression, including antiangiogenesis agents and the continuation of lapatinib or HT, was also equivalent and would not be expected to bias the results.
Taken together, these results are consistent enough to hypothesize that an overall survival benefit could be obtained by targeting EGFR/HER-2 inhibition in RCC. However, the significant difference in the EGFR-overexpressing population was not observed with a similar magnitude using the TTP end point. This may be due to the rapid progression of approximately 50% of patients at the first disease assessment (8 weeks), which could have contributed to an underpowered primary end point despite the divergence of the Kaplan and Meier curves at this time point. This may have masked the longer-term effect of lapatinib on the EGFR pathway observed in the survival end point.
In conclusion, although this large randomized trial was negative for the primary end point in the overall patient population, exploratory biomarker analysis has shown that second-line treatment with lapatinib seems to prolong overall survival relative to HT in patients with advanced RCC whose tumors overexpress EGFR.
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: Jason P. Gardner, GlaxoSmithKline (C); Frank Pétavy, GlaxoSmithKline (C); Iman El-Hariry, GlaxoSmithKline (C) Consultant or Advisory Role: Alain Ravaud, GlaxoSmithKline, Pfizer Inc, Bayer, Novartis, Wyeth (C); Robert Hawkins, GlaxoSmithKline (C); Peter Harper, GlaxoSmithKline (C); Martin Gore, GlaxoSmithKline (C) Stock Ownership: Jason P. Gardner, GlaxoSmithKline; Frank Pétavy, GlaxoSmithKline; Iman El-Hariry, GlaxoSmithKline Honoraria: Alain Ravaud, Pfizer Inc, Bayer; Hans von der Maase, Novo Nordisk, Pierre Fabre, Eli Lilly & Co, Roche, Bayer, Pfizer Inc; Peter Harper, GlaxoSmithKline; Bruno Audhuy, GlaxoSmithKline Research Funding: Alain Ravaud, GlaxoSmithKline, Roche; Martin Gore, GlaxoSmithKline Expert Testimony: None Other Remuneration: Alain Ravaud, Pfizer Inc, Bayer, Roche, Novartis; Hans von der Maase, Novo Nordisk, Pierre Fabre, Eli Lilly & Co, Roche, Bayer, Pfizer Inc
AUTHOR CONTRIBUTIONS
Conception and design: Alain Ravaud, Robert Hawkins, Jason P. Gardner, Niko Zantl, Peter Harper, Frank Pétavy, Martin Gore, Patrick Schöffski, Iman El-Hariry
Administrative support: Jason P. Gardner, Iman El-Hariry
Provision of study materials or patients: Alain Ravaud, Robert Hawkins, Jason P. Gardner, Hans von der Maase, Niko Zantl, Peter Harper, Frédéric Rolland, Bruno Audhuy, Jean-Pascal Machiels, Frank Pétavy, Martin Gore, Patrick Schöffski
Collection and assembly of data: Jason P. Gardner, Hans von der Maase, Frank Pétavy, Iman El-Hariry
Data analysis and interpretation: Alain Ravaud, Robert Hawkins, Jason P. Gardner, Hans von der Maase, Niko Zantl, Peter Harper, Frédéric Rolland, Bruno Audhuy, Jean-Pascal Machiels, Frank Pétavy, Martin Gore, Patrick Schöffski, Iman El-Hariry
Manuscript writing: Alain Ravaud, Robert Hawkins, Jason P. Gardner, Iman El-Hariry
Final approval of manuscript: Alain Ravaud, Robert Hawkins, Jason P. Gardner, Hans von der Maase, Niko Zantl, Peter Harper, Frédéric Rolland, Bruno Audhuy, Jean-Pascal Machiels, Frank Pétavy, Martin Gore, Patrick Schöffski, Iman El-Hariry
Appendix
The following investigators participated in this international multicenter trial:
Belgium: L. Dirix, B. Tombal, B. Sautois, F. Van Aelst, S. Van Belle, A. Van Oosterom, D. Verhoeven; Czech Republic: E. Kindlova, L. Petruzelka, H. Siffnerova, P. Vodvarka, J. Vydra; Denmark: H. von der Maase; Finland: P.-L. Kellokumpu-Lehtinen, S. Pyrhonen, K. Vasala; France: S. Abadie, B. Audhuy, M. Baciuchka, H. Cure, P. Fargeot, J.-M. Ferrero, R.-O. Fourcade, L. Geoffrois, D. Mayeur, S. Negrier, A. Ravaud, O. Rixe, F. Rolland, L. Salomon, U. Stein, J.-M. Tourani, N. Tubiana-Mathieu; Germany: P. Albers, O. Bolte, U. Brinkmann, M.-O. Grimm, J. Gschwend, Y. Ko, A. Krautschick, E.-D. Kreuser, C. Lippert, S. Loening, H.-G. Mergenthaler, S. Mueller, H. Riedmiller, S. Siemer, U. Wachter, M. Wirth, N. Zantl; Greece: V. Georgoulias, H. Kalofonos, D. Skarlos, G. Stathopoulos, I. Stergiou; Italy: G. Bruni, F. Roila, R. Rosso, C. Sternberg; Spain: L. Alonso, l.-P. Ares, J. Bellmunt, R. Colomer, Y. Fernandez, J.-G. Foncillas, J. Garcia del Muro, P. Gascon, A. Gonzalez del Alba; Sweden: E. Castellanos, U. Stierner; United Kingdom: A. Bahl, M. Gore, P. Harper, R. Hawkins, P. Patel, W. Steward.
Acknowledgments
We thank the patients who participated in this study and their families; the medical, nursing, and research staff; the independent monitoring committee; the monitors, staff, data managers, and statisticians (N. Compton, H. Hassani) at GlaxoSmithKline; and the editorial assistance of L. Pender from The Phillips Group Oncology Communications.
Footnotes
-
Both A.R. and R.H. contributed equally to this work.
Presented at the 42nd Annual Meeting of the American Society of Clinical Oncology, June 2-6, 2006, Atlanta, GA.
Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.
- Received September 18, 2007.
- Accepted January 25, 2008.
