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Journal of Clinical Oncology, Vol 26, No 12 (April 20), 2008: pp. 2013-2019 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.14.9930 Bevacizumab in Combination With Oxaliplatin-Based Chemotherapy As First-Line Therapy in Metastatic Colorectal Cancer: A Randomized Phase III Study
From the Memorial Sloan-Kettering Cancer Center, New York, NY; University of Sydney and Sydney Cancer Centre, Sydney, Australia; Hospital Clínico San Carlos, Madrid; Hospital Marques de Valdecilla, Santander, Spain; Vienna University Medical School, Vienna, Austria; Tel Aviv Sourasky Medical Center, Tel Aviv, Israel; Cancer Care Manitoba, St Boniface General Hospital, Winnipeg, Manitoba; Cross Cancer Institute, Edmonton, Alberta; CHUQ L'Hotel-Dieu De Quebec, Quebec, Canada; Russian Cancer Research Center, Moscow, Russian Federation; Chang-Gung Memorial Hospital, Tapei, Taiwan; F. Hoffmann-La Roche AG, Basel, Switzerland; and the Glasgow University, Glasgow, United Kingdom Corresponding author: Leonard B. Saltz, MD, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, Room H-917, New York, NY 10021; e-mail: saltzl{at}mskcc.org
Purpose To evaluate the efficacy and safety of bevacizumab when added to first-line oxaliplatin-based chemotherapy (either capecitabine plus oxaliplatin [XELOX] or fluorouracil/folinic acid plus oxaliplatin [FOLFOX-4]) in patients with metastatic colorectal cancer (MCRC). Patients and Methods Patients with MCRC were randomly assigned, in a 2 x 2 factorial design, to XELOX versus FOLFOX-4, and then to bevacizumab versus placebo. The primary end point was progression-free survival (PFS). Results A total of 1,401 patients were randomly assigned in this 2 x 2 analysis. Median progression-free survival (PFS) was 9.4 months in the bevacizumab group and 8.0 months in the placebo group (hazard ratio [HR], 0.83; 97.5% CI, 0.72 to 0.95; P = .0023). Median overall survival was 21.3 months in the bevacizumab group and 19.9 months in the placebo group (HR, 0.89; 97.5% CI, 0.76 to 1.03; P = .077). Response rates were similar in both arms. Analysis of treatment withdrawals showed that, despite protocol allowance of treatment continuation until disease progression, only 29% and 47% of bevacizumab and placebo recipients, respectively, were treated until progression. The toxicity profile of bevacizumab was consistent with that documented in previous trials. Conclusion The addition of bevacizumab to oxaliplatin-based chemotherapy significantly improved PFS in this first-line trial in patients with MCRC. Overall survival differences did not reach statistical significance, and response rate was not improved by the addition of bevacizumab. Treatment continuation until disease progression may be necessary in order to optimize the contribution of bevacizumab to therapy.
Bevacizumab (Avastin; Genentech Inc, South San Francisco, CA) is a humanized recombinant monoclonal antibody which binds to and blocks the activity of all isoforms of vascular endothelial growth factor-A (VEGF-A). A pivotal phase III study1 demonstrated that the addition of bevacizumab to irinotecan plus bolus fluorouracil and leucovorin conferred clinically significant improvements in overall survival (OS), progression-free survival (PFS), as well as response rate (RR), in patients with previously untreated metastatic colorectal cancer (MCRC). Bevacizumab was also shown to produce similar benefits in OS, PFS, and RR when combined with fluorouracil/folinic acid plus oxaliplatin (FOLFOX-4) in the second-line setting.2 We had initially begun a randomized phase III trial, designated NO16966, comparing the standard FOLFOX-43 regimen to the combination of capecitabine and oxaliplatin (XELOX).4 After the pivotal phase III data for bevacizumab became public in June 2003,1 the NO16966 protocol was amended to a randomized, 2 x 2 factorial design with two coprimary objectives. The first coprimary objective was to show the PFS noninferiority of XELOX with or without bevacizumab versus FOLFOX-4 with or without bevacizumab.1 The second coprimary objective, which is the focus of this report, was to evaluate the effect on PFS of bevacizumab versus placebo when combined with oxaliplatin-based chemotherapy (XELOX or FOLFOX-4).
Patient Population Patients age  18 years with histologically confirmed MCRC, one or more unidimensionally measurable lesions, who were not felt to be amenable to curative resection, with an Eastern Cooperative Oncology Group (ECOG) performance status of  1, and a life expectancy of longer than 3 months, were enrolled. No prior systemic therapy for MCRC or previous treatment with oxaliplatin or bevacizumab were allowed. Radiotherapy or surgery for MCRC was permitted if completed 4 weeks before random assignment.
Patients were required to have adequate hematologic/clotting, hepatic, and renal function. Pregnant or breast-feeding women were excluded. Other key exclusion criteria were: clinically significant cardiovascular disease; clinically detectable ascites; use of full-dose anticoagulants or thrombolytics; known CNS metastases; serious nonhealing wound, ulcer, or bone fracture; clinically significant bleeding diathesis or coagulopathy; and proteinuria
Treatment Plan Bevacizumab or placebo (bevacizumab vehicle) was administered as a 30- to 90-minute intravenous infusion before oxaliplatin at a dose of 7.5 mg/kg on day 1 of a 3-week cycle when given with XELOX or 5 mg/kg on day 1 of a 2-week cycle when given with FOLFOX-4. XELOX consisted of a 2-hour intravenous infusion of oxaliplatin 130 mg/m2 on day 1 followed by oral capecitabine 1,000 mg/m2 twice daily on days 1 through 14 (28 doses) of a 21-day cycle. The FOLFOX-4 regimen was as previously described.3 Treatment was supposed to be continued until disease progression (PD) or for 48 weeks (ie, up to 16 cycles of XELOX or 24 cycles of FOLFOX-4), whichever came first. Patients who completed the 48-week study treatment phase without PD were eligible to enter the poststudy treatment phase and continue treatment until PD. Patients whose tumors became operable, and underwent resection, were allowed to enter the poststudy treatment phase. The protocol specified that if one of the regimen components was discontinued due to toxicity, treatment could be continued with the remaining components.
Assessments
Tumor assessments (computed tomography scan, magnetic resonance imaging) were made within 28 days of starting study treatment and repeated after every 6 weeks of planned therapy (ie, after every two XELOX cycles or every three FOLFOX-4 cycles) and at the end of treatment. Response Evaluation Criteria in Solid Tumors guidelines6 were used to define all responses. Confirmation of response was required after Patients were evaluated for adverse events during therapy and until 28 days after the last study drug dose. Adverse events were graded according to National Cancer Institute Common Toxicity Criteria for Adverse Events, version 3. Predefined adverse events of special interest for bevacizumab were: proteinuria, hypertension, wound healing complications, thromboembolic events, gastrointestinal perforation, abscess or fistula, and bleedings.
Statistical Analysis As a first step, the analysis of pooled XELOX-containing versus pooled FOLFOX-4–containing arms was performed. If positive, an interaction test was performed on PFS to check for any interaction between the different treatment components (FOLFOX-4, XELOX, bevacizumab, nonbevacizumab). Independent of the interaction test, a clinical assessment of treatment effect was also performed. An interaction could be ruled out if the statistical interaction test was not significant and the clinical assessment revealed no clinically relevant difference. If an interaction was ruled out, the pooled analysis remained the primary analysis. If an interaction could not be ruled out, then results in the bevacizumab and nonbevacizumab treatment subgroups would have had to be considered. PFS was the primary study end point, and was defined as the time from random assignment to the first documentation of PD (per investigator assessment), or death from any cause. Patients undergoing curative metastasectomy were censored at the time for surgery. A general PFS definition was specified for the primary analysis, which included progression or death regardless of whether or not the patient remained on protocol therapy at the time of the event. Secondary efficacy end points were PFS using an on-treatment definition (same as general PFS; however, for events that occurred more than 28 days after the last intake of study medication, the patient was censored back to the date of last known nonprogression), OS, RR, duration of response, and time to treatment failure.
The analysis of study NO16966 was event-driven. The final analysis was to be done when 1,200 PFS events had occurred in the eligible patient population for the noninferiority comparison ensuring 90% power at an The study was performed in accordance with the Declaration of Helsinki and Good Clinical Practice Guidelines. Approval of the protocol was obtained at each participating site from an independent ethics committee or institutional review board. Written informed consent was obtained from all patients before study participation.
Patient Population Between February 2004 and February 2005, a total of 1,401 patients were randomly assigned in the 2 x 2 factorial (bevacizumab v placebo) part of the study that is reported here (Fig 1). A total of 1,400 patients made up the ITT population for the test of superiority of bevacizumab versus placebo (one patient was mistakenly randomly assigned twice). Baseline demographic and clinical characteristics were well balanced between treatment arms (Table 1).
Efficacy The cutoff date for the main analysis was January 31, 2006 (median duration of follow-up of 15.6 months); however, in order to present more mature information for OS, results are presented for a cutoff date of January 31, 2007 (median duration of follow-up of 27.6 months). Both a clinically relevant and statistically significant (P = .7025) treatment interaction was ruled out. Therefore, the planned pooled analysis of the bevacizumab- versus placebo-containing arms (FOLFOX-4 and bevacizumab plus XELOX and bevacizumab v FOLFOX-4 and placebo plus XELOX plus placebo) was the main analysis. Overall, 699 patients comprised the bevacizumab-containing arms and 701 comprised the placebo-containing arms. The data relating to the noninferiority of XELOX to FOLFOX-4 will be presented as a separate article.5 PFS, the primary study end point, was significantly increased with bevacizumab compared with placebo when combined with oxaliplatin-based chemotherapy (HR, 0.83; 97.5% CI, 0.72 to 0.95; P = .0023), the median PFS duration being 9.4 months with bevacizumab plus chemotherapy versus 8.0 months with placebo plus chemotherapy (Figure 2; Table 2). Using the prespecified secondary analysis of on-treatment PFS (ie, taking in account only progression or death events occurring within 28 days from the last dose of any component of study treatment), the median on-treatment PFS was 10.4 months with chemotherapy plus bevacizumab versus 7.9 months with chemotherapy plus placebo (HR, 0.63; 97.5% CI, 0.52 to 0.75; P < .0001; Table 2).
In a planned subset analysis, the impact of bevacizumab addition on PFS was assessed for each chemotherapy regimen. Using the general PFS definition, statistical superiority of bevacizumab versus placebo was evident in the XELOX subgroup (HR, 0.77; 97.5% CI, 0.63 to 0.94; P = .0026), but did not reach the significance level in the FOLFOX-4 subgroup (HR, 0.89; 97.5% CI, 0.73 to 1.08; P = .1871; online-only Table A1). Using the on-treatment PFS definition, significant results were evident in both the XELOX (HR, 0.61; 97.5% CI, 0.48 to 0.78; P < .0001) and FOLFOX-4 subgroups (HR, 0.65; 97.5% CI, 0.50 to 0.84; P = .0002). The details of other secondary end points are presented in Table 2. Median OS was 21.3 months with bevacizumab plus chemotherapy and 19.9 months with placebo plus chemotherapy. This difference did not reach statistical significance (HR, 0.89; 97.5% CI, 0.76 to 1.03; P = .077; Fig 3). For results by treatment subgroup see online-only TableA1.
RR, as assessed by investigators, was similar in the bevacizumab plus chemotherapy versus placebo plus chemotherapy groups (47% v 49%; odds ratio [OR], 0.90; 97.5% CI, 0.71 to 1.14; P = .31). According to the independent response review committee assessment, RR were also similar in both bevacizumab- and placebo-containing arms (38% v 38%; OR, 1.00; 97.5% CI, 0.78 to 1.28; P = .99). Fifty-nine patients (8.4%) in the bevacizumab-containing arms and 43 patients (6.1%) in the placebo-containing arms underwent an attempt at curative metastasectomy. Data on the number who achieved a complete R0 resection of all disease are not available at this time. There were no major imbalances between the treatment groups with respect to the use of second-line therapy: bevacizumab-containing arms (46%) and placebo-containing arms (53%). The most common agents used were: irinotecan (34% with bevacizumab v 42% with placebo); FU (23% v 31%); capecitabine (8% v 7%); cetuximab (9% v 12%); and bevacizumab (3% v 5%).
Treatment Exposure
Safety Table 4 presents details of adverse events leading to treatment discontinuation and predefined adverse events of special interest to bevacizumab. A higher proportion of patients discontinued study treatment because of adverse events in the bevacizumab-containing arms compared with the placebo-containing arms (30% v 21%). However, treatment discontinuations due to grade 3/4 adverse events were recorded in 21% of patients in the bevacizumab-containing arms versus 15% of patients in the placebo-containing arms, indicating that discontinuations due to grade 1/2 adverse events were not uncommon (10% v 6%). Further, most of these treatment discontinuations were attributable to chemotherapy-related events rather than events felt to be potentially related to bevacizumab; the most common reasons for treatment discontinuation were neurotoxicity, gastrointestinal events, general disorders, and hematologic events. Events felt to be potentially related to bevacizumab accounted for treatment discontinuation in 5% and 2% of patients in the bevacizumab- and placebo-containing arms, respectively.
The overall incidence of predefined grade 3/4 events felt to be potentially related to bevacizumab was 16% in the bevacizumab-containing arms and 8% in the placebo-containing arms (Table 4). The most common of these were thromboembolic events. The occurrence of grade 3/4 hypertension and bleeding was 2% to 4% of patients. Grade 3/4 gastrointestinal perforations, proteinuria, fistula/intra-abdominal abscess, and wound healing complications were all rare (< 1% of patients). No new bevacizumab-related safety signals were identified. Of the four gastrointestinal perforation events in the bevacizumab-containing arms, three events resolved without sequelae after stopping study treatment and one event was fatal. One of two gastrointestinal perforations that occurred among placebo-treated patients was fatal. Overall, 144 patients (21%) in the bevacizumab-containing arms and 104 patients (15%) in the placebo-containing arms received concomitant anticoagulant therapy at some time point during the study. The proportion of patients experiencing bleeding events in the bevacizumab-containing arms was similar in those with (24%) or without (28%) concurrent anticoagulation therapy. The incidence of grade 3/4 adverse events was approximately 5% higher among patients in the bevacizumab-containing arms versus the placebo-containing arms (Table 4). In general, the addition of bevacizumab caused no clinically relevant aggravation of grade 3/4 chemotherapy-related toxicity, although there were differences in gastrointestinal events (mainly diarrhea and vomiting; 32% v 27%), cardiac disorders (4% v < 1%), and hand-foot syndrome (7% v 3%) in the bevacizumab- versus placebo-containing arms. A by-patient review of cardiac events showed no common underlying pattern for the patients with these events. The remainder of the increase in grade 3/4 adverse events was accounted for by small increases in events with known associations with bevacizumab as discussed earlier (Table 4). The rate of treatment-related mortality within 28 days from last dose was similar in the bevacizumab and placebo groups (n = 14 [2.0%] and n = 10 [1.5%], respectively), as was the 60-day all-cause mortality rate (n = 14 [2.0%] and n = 11 [1.6%], respectively).
Taken together with previous randomized phase II and III studies conducted in the first-line setting,1,7-9 this study confirms that bevacizumab improves PFS when combined with chemotherapy for MCRC. The effect size was smaller than in previous studies,1,7 and, unlike two prior phase III trials,1,2 the observed trend in an improvement in OS did not reach statistical significance. Several factors may have contributed to this outcome. First, the overall treatment duration of bevacizumab and placebo (median  6 months) was similar in both treatment arms, while the duration of PFS was longer in the bevacizumab arm. The study protocol, like the prior protocols, allowed for treatment until PD. This finding of lack of treatment with bevacizumab until PD contrasts markedly with the previous studies, in which the duration of treatment in the bevacizumab arms was considerably longer (1.5 or 3 months) than in the control arms.1,2 The magnitude of benefit offered by bevacizumab in this study was considerably larger in the predefined on-treatment PFS analysis (HR, 0.63), which adjusts for preprogression alterations to study therapy (such as early study treatment discontinuation), than in the primary analysis, which used a general approach (HR, 0.83). In contrast to the bevacizumab arms, the two PFS definitions did not have any substantial impact on the Kaplan-Meier curves of the placebo arms. These findings suggest that the duration of bevacizumab therapy is likely to be important, and that treatment until PD may be necessary to maximize the clinical benefit derived from bevacizumab therapy. The reasons for the lack of treatment with bevacizumab or with chemotherapy until progression on this trial are not clear. One possibility is that when a cumulative toxicity, such as neurotoxicity or fatigue, reached a point at which the patient may have requested drug discontinuation, some investigators may not have fully appreciated that the protocol specifically permitted the discontinuation of one or more drugs while allowing for the continuation of others. Thus, for example, while discontinuation of oxaliplatin with continuation of fluoropyrimidine and bevacizumab was permitted, our analysis shows that this course of action was rarely taken.
In previous trials of bevacizumab in the first-line setting, RR increased by The OS benefit seen for bevacizumab in this trial did not reach statistical significance. Second- and further-line treatment regimens were comparable between the study arms, and only very few patients (3% in the bevacizumab and 5% in the placebo group) received bevacizumab in further lines. Therefore, it is unlikely that the survival results were confounded by cross-over. The lack of continuation of either bevacizumab or fluoropyrimidine (capecitabine or FU/leucovorin) until progression may have blunted the contribution of bevacizumab, thereby diminishing its impact on OS and PFS in this trial. The safety profile of bevacizumab documented in this trial was similar to that observed in previous clinical trials1,2,13 and large multinational observational studies.14,15 It is also notable that there was no increased bleeding risk in patients receiving bevacizumab and concomitant anticoagulation therapy compared with patients without concomitant anticoagulation. In conclusion, this trial reached its primary objective by showing a statistically significant increase in PFS through the addition of bevacizumab to oxaliplatin-based chemotherapy in first-line MCRC. No increase in RR was seen. The observed difference in OS did not reach statistical significance. Continuation of bevacizumab, and most likely fluoropyrimidine therapy as well, until PD appears to be critical with regards to the magnitude of clinical benefit derived from bevacizumab.
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: Florin Sirzén, Roche (C) Consultant or Advisory Role: Leonard B. Saltz, Genentech (C); Stephen Clarke, Roche (C); Eduardo Díaz-Rubio, Roche (C), sanofi-aventis (C); Arie Figer, Roche (C); Ralph Wong, Roche (C), sanofi-aventis (C); Jim Cassidy, Roche (C) Stock Ownership: None Honoraria: Stephen Clarke, Roche; Eduardo Díaz-Rubio, Roche, sanofi-aventis; Werner Scheithauer, Roche, sanofi-aventis; Arie Figer, Roche; Fernando Rivera, Roche; Felix Couture, Roche; Jim Cassidy, Roche Research Funding: Leonard B. Saltz, Roche, Genentech; Eduardo Díaz-Rubio, sanofi-aventis, Roche; Arie Figer, Roche; Fernando Rivera, Roche; Jim Cassidy, Roche Expert Testimony: None Other Remuneration: None
Conception and design: Florin Sirzén, Jim Cassidy Administrative support: Florin Sirzén Provision of study materials or patients: Leonard B. Saltz, Stephen Clarke, Eduardo Díaz-Rubio, Werner Scheithauer, Arie Figer, Ralph Wong, Sheryl Koski, Mikhail Lichinitser, Tsai-Shen Yang, Fernando Rivera, Felix Couture, Jim Cassidy Collection and assembly of data: Werner Scheithauer, Arie Figer, Fernando Rivera, Florin Sirzén Data analysis and interpretation: Florin Sirzén, Jim Cassidy Manuscript writing: Stephen Clarke, Eduardo Díaz-Rubio, Florin Sirzén, Jim Cassidy Final approval of manuscript: Leonard B. Saltz, Eduardo Díaz-Rubio, Werner Scheithauer, Arie Figer, Ralph Wong, Sheryl Koski, Fernando Rivera, Felix Couture, Florin Sirzén, Jim Cassidy
In addition to the investigators in the author list, we would like to acknowledge the following investigators who also participated in this trial: Australia: S. Begbie, I. Burns, P. Gibbs, D. Goldstein, P. Mainwaring, J. McKendrick, M. Michael, N. Pavlakis, T. Price, M. Schwartz, J. Shapiro, B. Stein, G. Van Hazel; Austria: J. Thaler; Brazil: C. Andrade, G. Ismael, A. Malzyner; Canada: J-P. Ayoub, S. Berry, R. Burkes, P. Dube, B. Findlay, C. Fitzgerald, A. Gurjal, D. Jonker, L. Kaizer, P. Klimo, B. Lesperance, P. Major, B. Melosky, L. Siu, M. Taylor, K. Virik, R. Wierzbicki, J. Wilson, A. Wong; China: F. Feng-Yi, Y. He, S. Jiao, J Li, R. Luo, L. Pan, S. Song, H. Wang, J. Xiong, B. Yu, S-Y. Yu; Czech Republic: D. Feltl, I. Kocakova, M. Kuta; Denmark: B.V. Jenson, P. Pfeiffer; Finland: P. Bono, P. Kellokumpu-Lehtinen, S. Pyrhoenen; France: F-X. Caroli-Bosc, B. Coudert, C. Debrigode, J-P. Delord, G. Des Guetz, J-Y. Douillard, E. Francois, G. Freyer, C. Garnier, M. Gil Delgado, F. Goldwasser, F. Husseini, P. Michel, S. Negrier, X. Pivot, P. Rougier; Germany: M. Clemens, A. Hochhaus, T. Hoehler, S. Kanzler, S. Kubicka, F. Kullmann, L. Mantovani, W-H. Schmiegel, H-J. Schmoll, R. Voigtmann; Guatemala: C.E. Hernandez-Monroy, L.M. Zetina Toache; Hong Kong: A. Chan; Hungary: M. Dank, I. Lang, T. Pinter, M. Szucs; Ireland: D. Fennelly, M. Keane, J. Kennedy, S. O'Reilly; Israel: A. Beny, A. Hubert, A. Sella, S. Stemmer; Italy: C. Boni, S. Brugnatelli, S. Cascinu, P.F. Conte, A. Contu, S. Monfardini, R. Rosso, S. Salvagni, A. Sobrero; Republic of Korea: Y.S. Park; Mexico: G. Calderillo, E. León; New Zealand: B. Robinson; Norway: L. Balteskard, T. Guren, H. Soerbye; Panama: E. Diaz-Correa; Portugal: S. Barroso, P. Cortes; Russian Federation: V.P. Kharchenko, G.M. Manikhas, V. Moiseenko; South Africa: G. Cohen, C. Kukard, J. Raats, C. Slabber, D. Vorobiof; Spain: J.E. Ales-Martinez, A. Anton Torres, J. Aparicio, E. Aranda, A. Cervantes, P. Escudero, J. Feliu, C. Fernandez-Martos, R. Garcia-Carbonero, P. Garcia-Alfonso, E. Gonzalez Flores, C. Gravalos, J. Maurel, M. Navarro-Garcia, R. Salazar, I. Sevilla, J. Tabernero; Sweden: B. Glimelius, H. Letocha, U. Loenn, D. Pedersen; Switzerland: M. Borner, A. Roth; Taiwan: T-Y. Chao, P-M. Chen, A.L. Cheng; Thailand: S. Chakrapee-Sirisuk, A.N. Kiatikajornthada, A. Sookprasert; Turkey: G. Demir, E. Goker; United Kingdom: E. Bessell, P. Chakraborti, F. Coxon, D. Cunningham, S. Falk, F. Daniel, R. Glynne-Jones, M. Hill, T. Iveson, A. Maraveyas, T. Maughan, D. Rea, L. Samuel, C. Topham; USA: N. Abramson, B. Amin, B. Bhaskar, L. Campos, R. Castillo, V. Chang, P. DeSimone, P. Eisenberg, J.A. Ellerton, T. Ervin, G. Frenette, J. Fuloria, H. Gomolin, M. Greenblatt, G. Gross, W.J.M. Hrushesky, D. Irwin, M. Kane, D. Kapur, B. Kasimis, K.S. Kumar, F-C. Lee, M.W. Lee, L. Martin, R. Mena, J. Neidhart, J. Pennacchi, E. Poplin, C. Redfern, R. Reiling, M Saleh, L. Schwartzberg, W. Sikov, A. Solky, P. Stella, S. Thomas, R. Vivacqua, R. Yanagihara.
Supported by Roche. Presented in part at the American Society of Clinical Oncology Gastrointestinal Cancers Symposium, Orlando, FL, January 19-21, 2007; and the 43rd Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, June 1-5, 2007. Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. Hurwitz H, Fehrenbacher L, Novotny W, et al: Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 350:2335-2342, 2004 2. Giantonio BJ, Catalano PJ, Meropol NJ: Bevacizumab in combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for previously treated metastatic colorectal cancer: Results from the Eastern Cooperative Oncology Group Study E3200. J Clin Oncol 25:1539-1544, 2007 3. de Gramont A, Figer A, Seymour M, et al: Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol 18:2938-2947, 2000 4. Cassidy J, Tabernero J, Twelves C et al: XELOX (capecitabine plus oxaliplatin): Active first-line therapy for patients with metastatic colorectal cancer. J Clin Oncol 22: 2084-2091, 2004 5. Cassidy J, Clarke S, Diaz-Rubio E, et al: Capecitabine plus oxaliplatin (XELOX) versus 5-fluorouracil plus oxaliplatin (FOLFOX-4) plus bevacizumab or placebo as first-line therapy in metastatic colorectal cancer: A randomized non-inferiority phase III study. J Clin Oncol doi:10.1200/JCO.2007.14.9898 6. Therasse P, Arbuck SG, Eisenhauer EA, et al: New guidelines to evaluate the response to treatment in solid tumors: European Organisation for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 92:205-216, 2000 7. Kabbinavar F, Hurwitz HI, Fehrenbacher L, et al: Phase II, randomized trial comparing bevacizumab plus fluorouracil (5-fluorouracil)/leucovorin (LV) with 5-fluorouracil/LV alone in patients with metastatic colorectal cancer. J Clin Oncol 21:60-65, 2003 8. Kabbinavar FF, Schulz J, McCleod M, et al: Addition of bevacizumab to bolus fluorouracil and leucovorin in first-line metastatic colorectal cancer: Results of a randomized phase II trial. J Clin Oncol 23:3697-3705, 2005 9. Kabbinavar FF, Hambleton J, Mass RD, et al: Combined analysis of efficacy: The addition of bevacizumab to fluorouracil/leucovorin improves survival for patients with metastatic colorectal cancer. J Clin Oncol 23:3706-3712, 2005 10. Miller KD, Chap LI, Holmes FA, et al: Randomized phase III trial of capecitabine compared with bevacizumab plus capecitabine in patients with previously treated metastatic breast cancer. J Clin Oncol 23:792-799, 2005 11. Sandler A, Gray R, Perry MC, et al: Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med 355: 2542-2550, 2006 12. Johnson DH, Fehrenbacher L, Novotny WF, et al: Randomized phase II trial comparing bevacizumab plus carboplatin and paclitaxel with carboplatin and paclitaxel alone in previously untreated locally advanced or metastatic non–small-cell lung cancer. J Clin Oncol 22:2184-2191, 2004 13. Hochster HS, Hart LL, Ramanathan RK, et al: Safety and efficacy of oxaliplatin/fluoropyrimidine regimens with or without bevacizumab as first-line treatment of metastatic colorectal cancer (mCRC): Final analysis of the TREE-study. J Clin Oncol 24:148s, 2006 (abstr 3510) 14. Hedrick E, Kozloff M, Hainsworth J, et al: Safety of bevacizumab plus chemotherapy as first-line treatment of patients with metastatic colorectal cancer: Updated results from a large observational registry in the United States (BriTE). J Clin Oncol 24:155s, 2006 (abstr 3536) 15. Van Cutsem E, Michael M, Berry S, et al: Preliminary safety and efficacy of bevacizumab with first-line FOLFOX, XELOX, FOLFIRI, and capecitabine for mCRC: First BEATrial. Proceedings of the 2007 Gastrointestinal Cancers Symposium, Orlando, FL, January 19-21, 2007 (abstr 346) Submitted October 30, 2007; accepted December 19, 2007.
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
level of 2.5%. At the same time, 985 events in ITT would have been expected to occur in the 2 x 2 factorial bevacizumab versus placebo comparison. Based on a hazard ratio (HR) of 0.75, this ensured 98% power for the pooled superiority comparison. 
