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Originally published as JCO Early Release 10.1200/JCO.2007.12.0949 on September 17 2007 © 2007 American Society of Clinical Oncology. Randomized Phase II Trial of Cetuximab, Bevacizumab, and Irinotecan Compared With Cetuximab and Bevacizumab Alone in Irinotecan-Refractory Colorectal Cancer: The BOND-2 Study
From the Department of Biostatistics; Gastrointestinal Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center; the Department of Medicine, Weill Medical College of Cornell University; Department of Medicine, New York University Cancer Institute, New York, NY; Division of Medical Oncology, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA; Department of Gastrointestinal Medical Oncology, University of Texas M.D. Anderson Cancer Center, Houston, TX; and the Chemotherapy Evaluation Program, Division of Cancer Treatment, National Cancer Institute, Bethesda, MD Address reprint requests to 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 We evaluated the safety and efficacy of concurrent administration of two monoclonal antibodies, cetuximab and bevacizumab, in patients with metastatic colorectal cancer. Patients and Methods This was a randomized phase II study in patients with irinotecan-refractory colorectal cancer. All patients were naïve to both bevacizumab and cetuximab. Patients in arm A received irinotecan at the same dose and schedule as last received before study entry, plus cetuximab 400 mg/m2 loading dose, then weekly cetuximab 250 mg/m2, plus bevacizumab 5 mg/kg administered every other week. Patients in arm B received the same cetuximab and bevacizumab as those in arm A but without irinotecan. Results Forty-three patients received cetuximab, bevacizumab, and irinotecan (CBI) and 40 patients received cetuximab and bevacizumab alone (CB). Toxicities were as would have been expected from the single agents. For the CBI arm, time to tumor progression (TTP) was 7.3 months and the response rate was 37%; for the CB arm, TTP was 4.9 months and the response rate was 20%. The overall survival for the CBI arm was 14.5 months and the overall survival for the CB-alone arm was 11.4 months. Conclusion Cetuximab and bevacizumab can be administered concurrently, with a toxicity pattern that seems to be similar to that which would be expected from the two agents alone. This combination plus irinotecan also seems to be feasible. The activity seen with the addition of bevacizumab to cetuximab, or to cetuximab plus irinotecan, seems to be favorable when compared with historical controls of cetuximab or cetuximab/irinotecan in patients who are naïve to bevacizumab.
Cetuximab is a human-murine chimeric monoclonal antibody that targets the epidermal growth factor receptor (EGFR).1 It has shown antitumor activity both alone and in combination with irinotecan in refractory colorectal cancer.2-4 Bevacizumab is a humanized monoclonal antibody directed against vascular endothelial growth factor A (VEGF-A).5 In conjunction with irinotecan, fluorouracil, and leucovorin chemotherapy, bevacizumab has been shown to improve response rate, progression-free survival, and overall survival, as compared with those patients receiving chemotherapy alone.6 Colorectal cancer (CRC) accounts for more than 55,000 deaths per year in the United States alone.7 Just more than a decade ago, fluorouracil (FU) was the only approved drug for this disease. Since 1996, six new agents (irinotecan, oxaliplatin, capecitabine, cetuximab, bevacizumab, and panitumumab) have been approved in the United States for the management of metastatic CRC. At the time that this study was undertaken, both cetuximab and bevacizumab remained investigational. Standard management of CRC consisted of use of fluoropyrimidines in conjunction with either oxaliplatin or irinotecan. After progression on both an irinotecan-based and an oxaliplatin-based schedule, no other standard therapy options existed at the time. Cetuximab was shown in an initial clinical trial to have a 22.5% response rate when combined with irinotecan in patients who had experienced clinical failure while receiving irinotecan.3 In a separate trial, single-agent cetuximab was shown to have a confirmed 8.8% response rate in this population as well.4 Both of these findings were confirmed subsequently in a randomized phase II trial, reported by Cunningham et al,2 that found 22.9% and 10.8% response rates for irinotecan plus cetuximab and cetuximab alone, respectively, in irinotecan-refractory patients. Unlike cetuximab, which was developed largely in the refractory setting, bevacizumab was investigated primarily as a component of front-line therapy. Hurwitz et al6 reported significant improvements in response rate, progression-free survival, and overall survival in patients receiving irinotecan, fluorouracil, and leucovorin plus bevacizumab, as compared with those receiving the chemotherapy combination alone. Thus, by mid-2003, the evidence was clear that both cetuximab and bevacizumab had the potential to contribute importantly to the management of patients with metastatic CRC. Furthermore, preclinical data had indicated that EGFR stimulation increases VEGF expression, thus providing a potential mechanistic hypothesis for synergy between the two agents.8-10 No trials, however, had combined these two agents. We therefore conducted a randomized phase II study, using the previous so-called BOND trial of Cunningham et al2 as a model; hence, this study has been widely referred to as the BOND-2 study. The primary objectives of this trial were to evaluate the safety and feasibility of concurrent administration of these two monoclonal antibodies in preparation for combination in front line metastatic studies, and to evaluate, in an exploratory manner, the activity of these two regimens relative to historical controls (the regimens not containing bevacizumab).
Patient Selection Eligible patients had histologic or cytologic confirmation of CRC, with measurable metastatic disease by Response Evaluation Criteria in Solid Tumors Group, and documentation of previous failure of at least one irinotecan-containing regimen for metastatic disease. Previous failure of therapy for metastatic disease was defined for this protocol as progression while receiving treatment or within 6 weeks after receiving the last dose of therapy. Failure for this assessment was defined as any enlargement of measurable or assessable lesion(s) or the development of any new lesion that was believed by the treating physician to represent clinical failure. Elevation of a tumor marker, such as carcinoembryonic antigen, was viewed as potentially supportive of disease progression but was not by itself accepted as adequate evidence for treatment failure. Documentation of failure by computed tomography, magnetic resonance imaging (MRI), or positron emission tomography scan was required. Patients who were intolerant of irinotecan despite dose attenuation were not eligible. Any number of prior regimens was allowed. Patients were required to have a, Eastern Cooperative Oncology Group performance status of 0 or 1, be age 18 years or older, and have a life expectancy more than 3 months. Adequate bone marrow and kidney function were required, and normal bilirubin was required. Patients were excluded if they had received prior bevacizumab, cetuximab, or other EGFR- or VEGF-directed agents, or if they required full-dose anticoagulation. This protocol was reviewed by the institutional review board of all participating institutions and all patients provided written informed consent before participation.
Chemotherapy
Treatment on each arm was continued until progression of disease, unacceptable toxicity, or until the patient withdrew consent. National Cancer Institute Common Adverse Event Criteria version 3.0 was used to assess toxicity. Although hematologic toxicity was not expected to be associated with cetuximab, cetuximab was to be withheld for grade 4 neutropenia, grade 3 thrombocytopenia, or febrile neutropenia, and was restarted when toxicity had resolved to grade Bevacizumab was to be discontinued for any grade 4 event felt to be related to bevacizumab, and for any arterial thrombotic event or GI perforation. Irinotecan was reduced by 20% for grade 3 neutropenia, thrombocytopenia, diarrhea, or other toxicity believed to be related to irinotecan, and was reduced by 40% for grade 4 toxicity.
Evaluation Criteria The primary objective of the study was to evaluate the effect of bevacizumab on time to tumor progression (TTP) when added to cetuximab plus irinotecan or to cetuximab alone, as compared with historical controls. Secondary objectives were evaluation of response rate and overall survival. Given that this was a randomized phase II study, direct comparisons between the two regimens were not the primary objectives of the study, although exploratory evaluation of the relative merits of these two approaches was permitted.
Statistical Considerations Previous data, reported on a similar patient population treated with cetuximab plus irinotecan, showed a median TTP of 4.0 months, and a median TTP of 1.6 months for these patients when treated with cetuximab alone. The addition of bevacizumab to a front-line, irinotecan-based regimen increased median TTP by 70%. A more modest impact was postulated for a third-line intervention. Thus, the incremental impact of bevacizumab was anticipated to yield a median TTP for CBI of approximately 6 months and a median TTP for CB of approximately 2.5 months.
With 35 patients in each arm, the study had sufficient power to estimate median TTP within ± 50%, thus providing a 95% CI of a hypothetical observed 6-month TTP from 4 to 9 months, and an observed hypothetical 2.4-month TTP from 1.6 to 3.6 months, assuming that progression times were distributed exponentially. This sample size also permitted an estimate of response rate to within ± 18% as the 95% CI, thereby allowing sufficient power to detect clinically significant improvement in objective response rate compared with historical controls. Patients were stratified by center, by performance status (0 v 1), and by serum albumin (
Patient Characteristics Eighty-three patients were treated on this trial at five participating institutions. Patient characteristics are outlined in Table 1. All patients had received prior irinotecan-containing chemotherapy, and the median number of prior regimens was three. Median age was somewhat older in the cohort receiving CBI; otherwise, patient characteristics were similar between the two treatment groups.
Toxicity Table 2 shows those toxicities typically associated with cetuximab. As would be anticipated, acneiform rash was the most commonly seen antibody-related toxicity. Two patients experienced severe headaches on the evening of the first dose of cetuximab, one of whom required hospital admission for parenteral opiate analgesics. These events occurred with the first dose of cetuximab only, on the evening before the first bevacizumab administration, so these events clearly do not represent an interaction between the two monoclonal antibodies.
Table 3 illustrates the toxicities more classically associated with cytotoxic agents such as irinotecan. Not surprisingly, neutropenia, diarrhea, and fatigue seem to be substantially greater in the cohort that received CBI versus the CB cohort that received the two monoclonal antibodies alone.
Serious Adverse Events One patient on arm A (CBI) developed a perforation of the small bowel. At operation, a necrotic metastatic tumor deposit was found to have eroded through the small bowel wall, resulting in the perforation. Another patient, who received the CB regimen, developed a perirectal fistula in the setting of progressive pelvic carcinomatosis. One other patient who received CBI was found to have a nonperforated duodenal ulcer on endoscopy. One patient who received CBI developed fatal enterococcal endocarditis. Two clear arterial thrombotic events occurred. One patient who received CBI developed a right frontal lacunar infarct. An MRI of the head also showed many chronic lacunar infarcts and chronic microvascular ischemic changes. Another patient who received the CB regimen, with a history of diabetes, hypertension, and anemia, developed a myocardial infarction on week 22 of therapy and died 16 days later. Given the advanced nature of disease and high degree of comorbidities in these patients, causality is difficult to attribute; however, the possibility that a study drug, particularly bevacizumab, contributed to these events, cannot be excluded.
Efficacy
The addition of the anti-VEGF monoclonal antibody bevacizumab to front-line chemotherapy,6 or to second-line chemotherapy in bevacizumab-naïve patients,11 has been demonstrated to improve progression-free and overall survival. Use of anti-EGFR monoclonal antibodies, either alone or in combination with irinotecan, has demonstrated clinically significant response rates in the chemotherapy-refractory setting, and has demonstrated improved progression-free survival over supportive care alone.2-4 Overall, however, neither of these so-called targeted therapies has lived up to preclinical expectations when administered as a single agent, and the contributions of these agents when administered in combination with chemotherapy to patients with CRC have been modest. Given the modest benefit with use of anti-VEGF or anti-EGFR antibodies alone, and the preclinical rationale for the combination of anti-EGFR and anti-VEGF strategies, the question of the feasibility of concurrent administration of anti-EGFR and anti-VEFG monoclonal antibodies became an important one. Our data indicate that the safety of the combination seems to be acceptable enough to warrant proceeding with additional studies. The toxicities encountered seem to be comparable to the toxicities that might have been expected from the individual agents. No clear synergistic toxicity was seen; however, the overall 20% grade 3 acne-like skin rash, although it is within the 95% CIs of prior reports, is somewhat higher than might have been expected from cetuximab alone. Larger randomized trials will be required to establish whether this represents a true modest increase in skin toxicity with the combination of bevacizumab and cetuximab. The toxicity added by irinotecan (predominantly diarrhea, neutropenia, and fatigue) is as would have been expected. The 28% incidence of grade 3 to 4 diarrhea in this previously treated population, in whom prior dose modifications of irinotecan presumably had been made if needed, is noteworthy. Whether this represents the expected toxicity of continued irinotecan in this population, or is indicative of a contribution from interaction with one or both of the antibodies, will need to be assessed in subsequent, larger trials. Efficacy comparisons against historical controls are always fraught with limitations; however, the primary statistical hypothesis of this randomized phase II study was based on historical comparisons, and the review of such comparisons suggests that the efficacy of both cetuximab alone and cetuximab plus irinotecan seems to be superior to the well-established historical controls. Two prior studies reported response rates of 23% for cetuximab plus irinotecan in irinotecan-refractory CRC patients, and a 4.1-month median TTP was reported.2,3 The 37% response rate and 7.3-month TTP seen in this trial with CBI in a similar patient population compares favorably with these historical controls. Similarly, and perhaps even more strikingly, the 20% response rate and the 4.9-month median TTP seen in this trial with CB compare favorably with the roughly 10% response rate and 1.5-month median TTP reported previously for cetuximab alone.2,4 It should be noted that the results of the current trial were achieved in patients who were bevacizumab naïve at the time of enrollment. Whether the addition of bevacizumab is beneficial in a patient who has experienced disease progression previously while receiving a bevacizumab-containing regimen remains unknown at this time. Given that this is a modest-sized, randomized, phase II trial, the results cannot be viewed as definitive, but rather as a hypothesis-generating trial that can serve as the basis for additional investigations. Our trial suggests that it is reasonable, from a safety standpoint, to proceed with larger scale trials of combined anti-EGFR and anti-VEGF monoclonal antibodies. The suggestion of superiority of the efficacy parameters, as compared with historical controls, supports continued exploration of this combination strategy. Several important trials are now underway to assess this paradigm further. Cancer and Leukemia Group B/Southwest Oncology Group trial 80405 is a National Cancer Institute intergroup trial that is offering participating patients the choice of infusional FU, leucovorin, and oxaliplatin (FOLFOX) or infusional FU, leucovorin, and irinotecan (FOLFIRI), and then randomly assigning them to receive concurrently either cetuximab, bevacizumab, or cetuximab plus bevacizumab. Another small, randomized, phase III trial, being led by Memorial Sloan-Kettering Cancer Center, is evaluating biweekly FU/leucovorin plus concurrent cetuximab and bevacizumab versus a control arm of FOLFOX plus bevacizumab. Although these trials will assess the activity and toxicities of concurrent cetuximab and bevacizumab therapies in the first-line management of CRC, another small trial currently is accruing patients to receive CBI who have experienced disease progression while receiving both irinotecan- and bevacizumab-containing regimens, to assess, in a preliminary manner, the contribution of bevacizumab after failure on a prior bevacizumab-containing regimen. Another first-line trial, known as the Panitumumab Advanced Colon Cancer Evaluation trial, has treated approximately 800 patients with FOLFOX plus bevacizumab and 200 patients with FOLFIRI plus bevacizumab, and randomly assigned them to receive or not receive concurrent panitumumab, another anti-EGFR monoclonal antibody. Preliminary reports regarding this trial, available at the time of this writing only as press releases,12 are deeply concerning. These preliminary reports note that in early analyses, there are no significant differences in response rates between the two arms, and that the panitumumab-containing arm shows inferior progression-free and overall survival as compared with the control arm. We see our trial, combining two monoclonal antibodies, as a first step toward using combinations of biologic or targeted therapies to eventually reduce or eliminate the role of cytotoxic agents in CRC treatment. The negative preliminary reports from the Panitumumab Advanced Colon Cancer Evaluation trial, however, serve as an important cautionary note. At present, we do not know whether the results encountered with panitumumab will generalize to cetuximab or not. The definitive clinical trials to address the relevant questions are in progress, and until the results of these trials are known, we should not make assumptions about the relative safety or efficacy of combined anti-EGFR plus anti-VEGF therapy, and should be extremely cautious regarding noninvestigational use of these combinations. Ultimately, the identification of particular patients (on the basis of molecular markers of sensitivity or resistance, either in the tumor or in the patient's genome), in the future, may help to select those who will benefit most, either from these individual agents or from combinations thereof.
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: None Consultant or Advisory Role: Leonard B. Saltz, Amgen (C), Genentech (C), YM BioSciences Inc (C), Sanofi-aventis (C), ImClone (U), Bristol Myers Squibb (U); Howard S. Hochster, Genentech (C), Imclone (C) Stock Ownership: None Honoraria: Howard S. Hochster, Genentech; Paulo M. Hoff, Roche, Merck KgaA Research Funding: Leonard B. Saltz, Genentech, Imclone, Bristol-Myers Squibb Co, Pfizer, Taiho, Bayer, Roche; Nancy E. Kemeny, Pfizer Expert Testimony: None Other Remuneration: None
Conception and design: Leonard B. Saltz, Mithat Gonen, Helen X. Chen Financial support: Helen X. Chen Provision of study materials or patients: Leonard B. Saltz, Heinz-Josef Lenz, Hedy L. Kindler, Howard S. Hochster, Scott Wadler, Paulo M. Hoff, Nancy E. Kemeny, Ellen M. Hollywood Collection and assembly of data: Leonard B. Saltz, Ellen M. Hollywood, Mithat Gonen, Marcus Quinones, Meroe Morse Data analysis and interpretation: Leonard B. Saltz, Helen X. Chen Manuscript writing: Leonard B. Saltz, Heinz-Josef Lenz, Howard S. Hochster Final approval of manuscript: Leonard B. Saltz, Heinz-Josef Lenz, Hedy L. Kindler, Howard S. Hochster, Scott Wadler, Paulo M. Hoff, Nancy E. Kemeny, Ellen M. Hollywood, Mithat Gonen, Marcus Quinones, Meroe Morse, Helen X. Chen
published online ahead of print at www.jco.org on September 17, 2007. Supported by the Cancer Therapy Evaluation Program (CTEP) of National Cancer Institute (NCI), under the collaborative agreement between CTEP, Genentech, ImClone, and Bristol-Myers Squibb Co: NCI Grants No. NO1-CM17105, NO1-CM17101, NO1-CM-17102, N01-CM-07003-CM74S, NO1-CM-17003. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. Brentjen R, Saltz L: Epidermal growth factor receptor blockade and treatment of solid tumor malignancies, in DeVita JVT, Helman S, Rosenberg SA (eds): Progress in Oncology. Boston, MA, Jones and Bartlett, 2002, pp 113-128 2. Cunningham D, Humblet Y, Siena S, et al: Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med 351:337-345, 2004 3. Saltz L, Rubin M, Hochster H, et al: Cetuximab (IMC-C225) plus irinotecan (CPT-11) is active in CPT-11-refractory colorectal cancer (CRC) that expresses epidermal growth factor receptor (EGFR). Proc Am Soc Clin Oncol 20:3a, 2001 (abstr 7) 4. Saltz LB, Meropol NJ, Loehrer PJ, et al: Phase II trial of cetuximab in patients with refractory colorectal cancer that expresses the epidermal growth factor receptor. J Clin Oncol 22:1201-1208, 2004 5. Ferrara N: Vascular endothelial growth factor: Basic science and clinical progress. Endocr Rev 25:581-611, 2004 6. 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 7. Jemal A, Seigel R, Ward E, et al: Cancer Statistics 2006. CA Cancer J Clin 56:106-130, 2006 8. Riedel F, Götte K, Li M, et al: EGFR antisense treatment of human HNSCC cell lines down-regulates VEGF expression and endothelial cell migration. Int J Oncol 21:11-16, 2002[Medline] 9. Ciardiello F, Caputo R, Branco R, et al: Inhibition of growth factor production and angiogenesis in human cancer cells by ZD1839 (Iressa), a selective epidermal growth factor receptor tyrosine kinase inhibitor. Clin Cancer Res 7:1459-1465, 2001 10. Viloria-Petit A, Crombet T, Jothy S, et al, Acquired resistance to the antitumor effect of epidermal growth factor receptor-blocking antibodies in vivo: A role for altered tumor angiogenesis. Cancer Res 61:5090-5101, 2001 11. Giantonio BJ, Catalano PJ, Meropol NJ, et al: High-dose bevacizumab improves survival when combined with FOLFOX4 in previously treated advanced colorectal cancer: Results from the Eastern Cooperative Oncology Group (ECOG) study E3200. J Clin Oncol 23:1s, 2005 (suppl; abstr 2)[CrossRef][Medline] 12. Amgen: Amgen discontinues Vectibix treatment in PACCE trial evaluating Vectibix as part of triple combination regimen. 2007. http://wwwext.amgen.com/media/media_pr_detail.jsp?year=2007&releaseID=977186 Submitted April 8, 2007; accepted June 27, 2007.
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2. For grade 3 or greater toxicities believed possibly or likely to be related to cetuximab, cetuximab was withheld until resolution of the toxicity and then reduced by 50 mg/m2 when restarted. Cetuximab was to be withheld for the first incidence of grade 3 acne-like rash, but was not reduced for this first incidence. If the rash again subsequently reached grade 3, then cetuximab was withheld until the rash improved to grade 
