epic: phase iii trial of cetuximab plus irinotecan after fluoropyrimidine and oxaliplatin failure in patients with metastatic colorectal cancer EPIC: Phase III Trial of Cetuximab Plus Irinotecan After Fluoropyrimidine and Oxaliplatin Failure in Patients With Metastatic Colorectal Cancer

EPIC: Phase III Trial of Cetuximab Plus Irinotecan After Fluoropyrimidine and Oxaliplatin Failure in Patients With Metastatic Colorectal Cancer

  1. Howard A. Burris III
  1. From the Department of Medical Oncology, Ospedale San Martino, Genoa; Department of Oncology and Hematology, Policlinico, Modena, Italy; Department of Medical Oncology, Hospital Clínic Barcelona, CIBERehd, Barcelona; Hospital Universitario Marques de Valdecilla, Santander, Spain; Clinical Division of Oncology, Department of Medicine I and Cancer Center, Medical University Vienna, Austria; Caritasklinik St. Theresia, Saarbrücken; Department of Hematology/Oncology, Klinikum Kassel, Kassel; Oncological Practice, Magdeburg; Merck KGaA, Darmstadt, Germany; Department of Radiotherapy and Oncology, University Hospital Motol, Prague, Czech Republic; Department of Medical Oncology, INSERM U645, University Hospital, Besançon, France; St Luke's Oncology Centre, Guildford, United Kingdom; Kaiser Permanente Medical Center Northern California, Vallejo; Division of Medical Oncology, University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, CA; Florida Oncology Associates, Jacksonville, FL; M.D. Anderson Cancer Center, Houston, TX; Bristol-Myers Squibb, Wallingford, CT; and the Sarah Cannon Research Institute and Tennessee Oncology, PLLC, Nashville, TN
  1. Corresponding author: Alberto F. Sobrero, MD, Department of Medical Oncology, Ospedale San Martino, Genoa, 16132, Italy; e-mail: alberto.sobrero{at}hsanmartino.liguria.it
 
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Abstract

Purpose To determine whether adding cetuximab to irinotecan prolongs survival in patients with metastatic colorectal cancer (mCRC) previously treated with fluoropyrimidine and oxaliplatin.

Patients and Methods This multicenter, open-label, phase III study randomly assigned 1,298 patients with epidermal growth factor receptor–expressing mCRC who had experienced first-line fluoropyrimidine and oxaliplatin treatment failure to cetuximab (400 mg/m2 day 1 followed by 250 mg/m2 weekly) plus irinotecan (350 mg/m2 every 3 weeks) or irinotecan alone. Primary end point was overall survival (OS); secondary end points included progression-free survival (PFS), response rate (RR), and quality of life (QOL).

Results Median OS was comparable between treatments: 10.7 months (95% CI, 9.6 to 11.3) with cetuximab/irinotecan and 10.0 months (95% CI, 9.1 to 11.3) with irinotecan alone (hazard ratio [HR], 0.975; 95% CI, 0.854 to 1.114; P = .71). This lack of difference may have been due to post-trial therapy: 46.9% of patients assigned to irinotecan eventually received cetuximab (87.2% of those who did, received it with irinotecan). Cetuximab added to irinotecan significantly improved PFS (median, 4.0 v 2.6 months; HR, 0.692; 95% CI, 0.617 to 0.776; P ≤ .0001) and RR (16.4% v 4.2%; P < .0001), and resulted in significantly better scores in the QOL analysis of global health status (P = .047). Cetuximab did not exacerbate toxicity, except for acneform rash, diarrhea, hypomagnesemia, and associated electrolyte imbalances. neutropenia was the most common severe toxicity across treatment arms.

Conclusion Cetuximab and irinotecan improved PFS and RR, and resulted in better QOL versus irinotecan alone. OS was similar between study groups, possibly influenced by the large number of patients in the irinotecan arm who received cetuximab and irinotecan poststudy.

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INTRODUCTION

Management of metastatic colorectal cancer (mCRC) has evolved over the past decade. Patients receiving irinotecan (Camptosar; Pfizer Inc, New York, NY),1-4 oxaliplatin (Eloxatin; Sanofi-aventis U.S. LLC, Bridgewater, NJ)5-7 and fluorouracil (FU) achieve the best outcomes (median survival (MS), approximately 21 months), regardless of treatment sequence.7,8 Biologic therapies provide further improvements. The antiangiogenic monoclonal antibody bevacizumab (Avastin; Genentech Inc, South San Francisco, CA) improves survival in bevacizumab-naïve patients when added to first-line9 or second-line chemotherapy,10 but seems inactive in refractory disease.10,11 Biologics targeting the epidermal growth factor receptor (EGFR) are effective in disease refractory to FU, irinotecan, and oxaliplatin.12,13

Cetuximab (ERBITUX; ImClone Systems Inc, New York, NY, and Bristol-Myers Squibb Co, Princeton, NJ), a chimeric monoclonal immunoglobulin 1 that binds to the EGFR, blocks signal transduction, modulates tumor growth,14,15 and may mediate antibody-dependent cell-mediated cytotoxicity.16 Cetuximab and irinotecan have produced among the highest response rates (RR; approximately 23%) observed in refractory patients, and the pattern of activity in irinotecan-refractory patients suggests cetuximab restores chemosensitivity.14 Cetuximab is also active as a single agent, producing objective RR between 9% and 12%,12,14,17 and improving survival when compared with best supportive care in refractory patients.18 The role of cetuximab-based combinations in first-line therapy is under investigation.19,20

The ERBITUX Plus Irinotecan for Metastatic Colorectal Cancer (EPIC) study was designed to determine whether adding cetuximab to irinotecan as second-line therapy would prolong survival in irinotecan-naïve patients with EGFR-expressing mCRC. Second-line was defined as failure of prior fluoropyrimidine and oxaliplatin therapy.

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PATIENTS AND METHODS

Study Design and Eligibility Criteria

In this open-label, randomized, phase III study, patients from 221 sites worldwide were randomly assigned 1:1 to receive cetuximab/irinotecan or irinotecan alone. The randomization was stratified by study site and Eastern Cooperative Oncology Group (ECOG) performance status (PS, 0 to 1 v 2).

Eligibility required bidimensionally measurable (≥ 1 tumor with 1 diameter ≥ 20 mm and the other ≥ 10 mm), histologically documented mCRC with immunohistochemical evidence of EGFR expression. Failure (disease progression/discontinuation due to toxicity) within 6 months of the last-dose of first-line fluoropyrimidine and oxaliplatin treatment for metastatic disease was required. Previous irinotecan or anti-EGFR therapies were excluded; prior bevacizumab was allowed.

This study was performed after approval by a local human investigations committee and in accord with an assurance filed with and approved by the department of health and human services where appropriate. Informed consent was obtained from each participant.

Treatment

The only irinotecan regimen approved by the US Food and Drug Administration and the European Medicines Agency for pretreated patients at the time of design was irinotecan monotherapy (every 3 weeks), therefore it was chosen as comparator. Patients assigned to the irinotecan and cetuximab arm received an initial 400-mg/m2 cetuximab dose (2-hour intravenously [IV]), and then 250 mg/m2 (1-hour IV) weekly, preceded by premedication with antihistamine. Irinotecan 350 mg/m2 (90-minute IV; 300 mg/m2 for patients ≥ 70 years, those with ECOG PS of 2, or with prior pelvic/abdominal irradiation) was administered every 3 weeks in both treatment arms, starting 1 hour after cetuximab-infusion completion for patients in the cetuximab arm. Treatment continued until disease progression or unacceptable toxicity. There were no poststudy treatment limitations.

Assessments

Tumor response was evaluated every 6 weeks (computed tomography/magnetic resonance imaging scans of abdomen, pelvis, and chest; x-rays acceptable to confirm bone-scan findings) using modified WHO criteria. Objective responses required a ≥ 50% reduction (relative to baseline) in the area of all index lesions (investigator selected), confirmed ≥ 4 weeks later. Disease progression was defined by a 25% increase in the index-lesion area relative to the smallest area recorded, by progression of nonmeasurable lesions, or by appearance of new lesions. Quality of life (QOL) was assessed at baseline, after 3 weeks, and then every 6 weeks until the first post-therapy follow-up visit using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C-30,21 administered before study-related procedures or clinician assessments. Physical examinations and toxicity assessments were performed before each cycle and after therapy completion. Blood counts were evaluated weekly during the first two cycles and then before each cycle. A protocol amendment in February 2005 initiated routine monitoring of blood magnesium levels, as part of laboratory testing. Adverse events and laboratory examinations were graded using the National Cancer Institute Common Toxicity Criteria version 2.0. Follow-up assessment was conducted 6 weeks after treatment completion. Subsequent therapy and survival were monitored every 3 months.

Interim Analyses

Two independent interim analyses (after 400 and 800 randomly assigned patients) were conducted by the data safety monitoring board: a safety review, and a survival comparison/safety review, respectively. Both result sets were unknown by the sponsors until after database lock.

Statistical Analyses

The primary study end point was survival. This study required 850 events to complete and had 90% power for demonstrating a statistically significant survival difference, assuming a true HR (cetuximab and irinotecan to irinotecan) of 0.80. An O'Brien and Fleming type α spending function was used to ensure an overall, two-sided, type I error rate of 5%. Survival was compared between treatment arms using a two-sided log-rank test stratified by ECOG PS (0 to 1 v 2). This analysis was supplemented by Kaplan-Meier curves, and estimates of OS, HR, and associated confidence intervals (HR CI level was adjusted for the interim analysis).

Progression-free survival (PFS; defined as time to progression or death, and evaluated similar to survival) and rates of tumor response were determined from study-investigator assessments, without independent review for these secondary end points. Tumor response was compared between treatment arms using a Cochran-Mantel-Haenszel test stratified by ECOG PS (0 to 1 v 2). The duration of treatment was the period from the first dose until the last plus 21 days for irinotecan and plus 7 days for cetuximab. Time to response was computed for those patients with a response (complete or partial).

European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C-30 score changes from baseline were compared between treatment arms by a Wei-Lachin test. Adverse events were categorized using the MedDRA dictionary, version 9.1. Analyses of survival, PFS, tumor response, and QOL were done on an intent-to-treat basis. Safety analyses were restricted to treated subjects.

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RESULTS

Patient Characteristics and Disposition

From May 2003 to February 2006, 1,587 patients were enrolled; 1,410 with EGFR-positive tumors by immunohistochemistry. After meeting all eligibility criteria, 1,298 patients were randomly assigned, 648 to cetuximab and irinotecan and 650 to irinotecan alone (Fig 1). Demographic and clinical characteristics of study patients were well balanced between treatment arms (Table 1).

Fig 1.
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Fig 1.

Patient disposition.

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Table 1.

Patient Demographics and Clinical Characteristics

Treatment Exposure

Median treatment duration was longer for the cetuximab and irinotecan combination: cetuximab for 14.0 weeks (range, 0.7 to 97.9), irinotecan for 13.1 weeks (range, 0.7 to 89.1), versus 9.9 weeks for irinotecan alone (range, 0.4 to 71.0). Irinotecan delivery (treatment delay rates and median dose intensity) was comparable in the two groups, but the irinotecan cumulative dose was higher with cetuximab and irinotecan (median, 1,395 v 1,048 mg/m2).

Reductions in irinotecan dose were more frequent in the cetuximab and irinotecan arm (43.7% v 36.2%), mostly due to toxicity such as gastrointestinal events (13.2% v 9.5%) and delayed hematologic recovery (12.5% v 9.7%). The cetuximab dose was reduced in 129 patients (20.2%), including 28 patients (4.4%) due to skin toxicity.

Efficacy

At the time of the data cutoff, 203 patients in the cetuximab and irinotecan arm (31.3%) and 221 patients in the irinotecan arm (34.0%) were alive. OS was comparable between treatments (log-rank P = .71): the HR was 0.975 (95% CI, 0.854 to 1.114, adjusted for an interim analysis). MS was 10.7 months (95% CI, 9.6 to 11.3) with cetuximab/irinotecan and 10.0 months (95% CI, 9.1 to 11.3) with irinotecan alone (Fig 2). The survival results may have been confounded by poststudy therapy: 46.9% of patients assigned to the irinotecan arm went on to receive cetuximab poststudy (87.2% of those, in combination with irinotecan).

Fig 2.
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Fig 2.

Kaplan-Meier analysis of overall survival.

PFS was significantly longer in the cetuximab and irinotecan arm (log-rank P ≤ .0001): the HR of cetuximab/irinotecan to irinotecan was 0.692 (95% CI, 0.617 to 0.776), indicating a 31% reduction in risk of progression. Median PFS was 4.0 months (95% CI, 3.2 to 4.1) with cetuximab and irinotecan and 2.6 months (95% CI, 2.1 to 2.7) with irinotecan alone; 6-month PFS rates were 27.4% (95% CI, 23.9 to 30.9) and 16.3% (95% CI, 13.3 to 19.2), respectively, and 9-month PFS rates were 12.6% (95% CI, 10.0 to 15.3) versus 6.5% (95% CI, 4.5 to 8.5; Fig 3).

Fig 3.
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Fig 3.

Kaplan-Meier analysis of progression-free survival.

The overall RR with cetuximab and irinotecan was 16.4% (95% CI, 13.6 to 19.4), compared with 4.2% (95% CI, 2.8 to 6.0) with irinotecan alone (P < .0001; Table 2). Nine patients receiving the combination had complete responses versus 1 patient receiving irinotecan alone. The median time to response (2.5 v 2.7 months) and the median duration of response (5.7 v 5.5 months) did not differ between treatment groups.

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Table 2.

Treatment Responses

Consistent with the overall results, predetermined subgroup analyses showed superior PFS and RR with cetuximab and irinotecan regardless of age (< 65 v ≥ 65 years), sex, race, and PS strata (not shown).

QOL

Cetuximab and irinotecan were significantly more effective in maintaining overall QOL. Advantages were seen with cetuximab and irinotecan in 10 of 15 scales, including fatigue (P = .005), nausea/vomiting (P < .001), insomnia (P = .04), pain (P < .001), and diarrhea (P = .02), as well as domains such as global health status (P = .047), physical functioning (P = .002), role functioning (P = .003), emotional functioning (P = .002), and cognitive functioning (P < .001) (Fig 4); no differences were seen in the social-functioning domain (P = .774). Compliance with the questionnaire was not significantly different between treatment arms (56.3% v 56.1% at 15 weeks); the differences in QOL, apparent by the end of the first treatment cycle, remained throughout the study.

Fig 4.
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Fig 4.

Quality-of-life analysis across treatment arms. Change from baseline in (A) global health status, (B) physical functioning, (C) emotional functioning, (D) fatigue, (E) diarrhea, and (F) pain on the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C-30. CET, cetuximab; IRI, irinotecan.

Safety

Overall, the safety profile of the cetuximab and irinotecan combination was consistent with prior studies,14 without meaningful increases in toxicity over irinotecan alone except for acneform rash and diarrhea. Ninety-seven patients died within 30 days of the last treatment: 57 patients in the cetuximab and irinotecan arm (8.9%) and 40 patients in the irinotecan arm (6.4%). Seven deaths (five and two patients, respectively) were attributed to study drug toxicity.

neutropenia and diarrhea were the most common grade 3/4 adverse events, consistent with the profile of irinotecan; both occurred more frequently with cetuximab and irinotecan (Table 3). Severe febrile neutropenia was reported in 8.3% and 6.4% of patients in the cetuximab and irinotecan and irinotecan groups, respectively. Grade 3/4 infusion reactions occurred in 1.4% of cetuximab and irinotecan patients and 0.8% of those on irinotecan alone. Drug-related acneform rash occurred in most patients (76.3%) receiving cetuximab, becoming severe in 51 cases (8.0%). hypomagnesemia (and other electrolyte imbalances) was more frequent with cetuximab and irinotecan (33.8% v 8.4% with irinotecan), but with few severe cases (3.3% v 0.4%) and no clinically relevant adervse effects.

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Table 3.

Most Common Drug-Related Nonhematologic AEs and On-Study Laboratory Abnormalities

Rates of toxicity-related therapy discontinuation were similar across treatment arms (6.5% for irinotecan and cetuximab v 4.8% for irinotecan). Hospitalizations for gastrointestinal (15.4% v 12.6%) and hematologic toxicities (9.7% v 7.9%) were slightly higher in the cetuximab and irinotecan arm.

Drug-related serious adverse events were reported in 186 patients (29.2%) and 142 patients (22.6%) in the cetuximab and irinotecan and irinotecan groups, respectively, most commonly diarrhea (11.9% v 9.4%), febrile neutropenia (7.7% v 6.2%), and vomiting (4.4% v 3.3%).

Post-Hoc Analyses

Two analyses were done in order to elucidate the potential effect of poststudy therapy. An exploratory analysis evaluated survival in patients randomly assigned before cetuximab received regulatory approval in each study country (n = 459), censoring alive subjects once cetuximab was approved in their markets. MS was 10.5 months in the cetuximab and irinotecan arm and 8.6 months in the irinotecan alone arm (Fig A1A, online only). This difference was not statistically significant (P = .60). This exploratory analysis, however, was highly underpowered (number of events, 123).

A second post hoc exploratory analysis was a nonrandomized examination of survival outcomes in patients from the irinotecan-only arm. Those without any poststudy therapy (n = 229) had a MS of 3.9 months (95% CI, 3.5 to 4.9), those treated poststudy, but without cetuximab (n = 116) had a MS of 10.1 months (95% CI, 9.0 to 13.2), and MS for those who received subsequent cetuximab (n = 305) was 13.0 months (95% CI, 12.2 to 15.0; Fig A1B, online only). There is an inherent potential for bias in a nonrandomized comparison such as this, however, the two patient subgroups of interest (those receiving subsequent therapy with or without cetuximab) seemed to be reasonably balanced. Baseline features (such as age, sex, or race) were similar in both groups, as were prognostic characteristics, such as time until discontinuation of study therapy (median, 2.8 months for both groups) and the distribution of performance status at time of last study dose (PS 0 for 46% and 47% of patients, PS 1 for 50% in both groups, and PS 2 for 4% and 3%, respectively). In the interest of completeness, a similar analysis was carried out in the experimental arm. For patients treated with cetuximab and irinotecan on study who did not receive any poststudy therapy (n = 279), MS was 6.31 months (95% CI, 5.3 to 7.1); for those that received therapy poststudy but without cetuximab (n = 296), MS was 13.0 months (95% CI, 11.6 to 13.9); finally, for patients in the experimental arm receiving poststudy therapy with cetuximab (n = 73), MS was 16.2 months (95% CI, 12.8 to 27.4; Fig A1C, online only). For this posthoc analysis of survival in patients in the experimental arm that went to receive poststudy therapy, the median time to study-therapy discontinuation for patients with or without poststudy cetuximab was 4.8 and 4.1 months, respectively; the distribution of performance status at time of last study dose was PS 0 for 43.8% and 55.7% of patients, PS 1 for 48.0% and 43.6%, and PS 2 for 8.2% and 1.7%, respectively.

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DISCUSSION

EPIC demonstrated significant improvements in PFS and RR with the addition of cetuximab to irinotecan. This study, however, failed to meet its primary end point, showing no statistically significant differences in survival between cetuximab and irinotecan and irinotecan alone.

Postprotocol treatment may have affected survival, given the substantial proportion (46.9%) of initial irinotecan patients who subsequently received a cetuximab-based regimen, an effective standard treatment after irinotecan failure.14 Posthoc exploratory analyses suggest that poststudy cetuximab may have reduced any potential difference across treatment arms, prolonging survival in the patients who received it. These findings are inconclusive, but consistent with those from the recent phase III NCIC-017 study, in which cetuximab significantly improved survival compared to best supportive care (HR, 0.766; 95% CI, 0.637 to 0.921; P = .0046) in patients previously treated with a fluoropyrimidine, irinotecan, and oxaliplatin.18 The lack of survival difference, however, may not be entirely due to a cross-over effect, since, in other settings, trials have documented survival differences even after cross-over.22,23

The effect of poststudy therapies on early-line clinical trials in mCRC is not unprecedented,24 with some authors questioning the reliability of OS versus PFS as end point in early therapy settings.8,25 Survival was the appropriate choice as primary end point for a trial designed to affect clinical practice. However, this study illustrates the challenges of studying commercially available agents early in the course of disease, and the complicating effects of postprotocol factors.

The improved efficacy in secondary end points that are well-documented and valid in mCRC,25,26 and the QOL results obtained with cetuximab must not be overlooked. In this trial, adding cetuximab to irinotecan reduced the risk of progression by 31%, and improved median PFS by 55%, and RR by nearly four-fold, including a higher number of complete responses (nine v first). The QOL assessments also support this benefit. Global health status as well as physical, emotional, and cognitive functioning were significantly better with cetuximab and irinotecan. These results are the best reported to date after oxaliplatin plus FU and leucovorin (FOLFOX) failure.7

The safety profile of cetuximab plus irinotecan in this study was manageable, predictable, and consistent with prior studies.14 The addition of cetuximab to irinotecan did not result in meaningful increases in toxicity, except for acneform rash, diarrhea, and electrolyte imbalances. Whether these increases are due to cetuximab itself, or a byproduct of the higher cumulative irinotecan dose with the combination, is unclear, and these findings warrant careful evaluation of the patients appropriate for this regimen. Nonetheless the nearly 50% rate of patients still receiving combination treatment at 15 weeks further reassures of its tolerability.

Several caveats surround these results, apart from the potential effect of poststudy cross-over. The absence of independent radiology-review system is a weakness of particular concern given the weight of the PFS and RR end points in the final results of the study. Nevertheless, the differences observed make a compelling argument for the therapeutic effect of cetuximab. The application of a self-reported questionnaire to assess QOL in a nonblinded study can also be considered problematic. It could be argued, however, that this is a method to assess patients' individual experiences; in this case, the consistency of the results across most scales probably points to a bona-fide effect. Also, this standard tool lacks specific acneform-rash scores, a limiting aspect for studies of EGFR inhibitors. Until this deficiency is addressed, scores such as social functioning may provide a partial indication of the potential effect of acneform rash in the QOL of patients.

It is almost certain that outcomes with cetuximab will be enhanced by patient selection. Remarkably, randomized trastuzumab trials conducted in preselected patients with breast cancer could demonstrate survival benefits, even after a cross-over.23 Recent reports indicate that the presence of mutations on the KRAS gene is a strong predictor of nonresponsiveness to cetuximab,27-29 and that overexpression of the EGFR ligands amphiregulin and epiregulin may be a robust marker of response.28 While trials are ongoing to validate these biomarkers, whether a pronounced benefit could be documented in any of these subpopulations in EPIC is under study.

As the evaluation of cetuximab continues, with ongoing or recently-completed randomized trials in first-line (Cancer and Leukemia Group B 80203, Oxaliplatin and Cetuximab in First-Line Treatment of Metastatic Colorectal Cancer, and Cetuximab Combined with Irinotecan in First-Line Therapy for Metastatic Colorectal Cancer),19,20,30 with bevacizumab (Cancer and Leukemia Group B 80405), and in the adjuvant setting (North Central Cancer Treatment Group N0147), the data from this EPIC study join the recent NCIC-017 results, showing that cetuximab provides OS and PFS, as well as RR and QOL, benefits in multirefractory patients.18 EPIC is the largest comparative trial investigating the efficacy and tolerability of cetuximab added to irinotecan after FOLFOX failure, demonstrating PFS and RR improvements in irinotecan-naïve patients consistent with prior studies in refractory disease. With these results, the inclusion of cetuximab among the core agents in the optimal management of mCRC8,31 is well supported. Ongoing studies will further define the optimal use of cetuximab throughout CRC treatment settings.

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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: Oliver Kisker, Merck KGaA (C); Angela Zubel, Merck KGaA (C); Christiane Langer, Bristol-Myers Squibb (C); Justin Kopit, Bristol-Myers Squibb (C) Consultant or Advisory Role: Alberto F. Sobrero, Merck KGaA (C), Pfizer (C), Roche (C), Sanofi-aventis (C), Amgen (C); Heinz-Josef Lenz, ImClone Systems (C), Bristol-Myers Squibb (C), Merck KGaA (C); Howard A. Burris III, Bristol-Myers Squibb (C) Stock Ownership: Christiane Langer, Bristol-Myers Squibb; Justin Kopit, Bristol-Myers Squibb Honoraria: Alberto F. Sobrero, Merck KGaA, Pfizer, Amgen, Roche, Sanofi-aventis; Werner Scheithauer, Merck KGaA, Pfizer; Howard A. Burris III, Bristol-Myers Squibb Research Funding: Alberto F. Sobrero, Merck KGaA; Werner Scheithauer, Merck KGaA; Cathy Eng, Bristol-Myers Squibb, Genentech, Novartis, Sanofi-aventis, AstraZeneca, Pfizer; Heinz-Josef Lenz, Bristol-Myers Squibb; Gabriele Luppi, Merck KGaA, Bristol-Myers Squibb, ImClone Systems Expert Testimony: None Other Remuneration: None

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AUTHOR CONTRIBUTIONS

Conception and design: Alberto F. Sobrero, Oliver Kisker, Angela Zubel, Christiane Langer, Justin Kopit

Provision of study materials or patients: Alberto F. Sobrero, Joan Maurel, Louis Fehrenbacher, Werner Scheithauer, Yousif A. Abubakr, Manfred P. Lutz, M. Eugenia Vega-Villegas, Cathy Eng, Ernst U. Steinhauer, Jana Prausova, Heinz-Josef Lenz, Christophe Borg, Gary Middleton, Hendrick Kröning, Gabriele Luppi, Howard A. Burris III

Collection and assembly of data: Louis Fehrenbacher, Werner Scheithauer, Yousif A. Abubakr, Manfred P. Lutz, M. Eugenia Vega-Villegas, Cathy Eng, Gary Middleton, Justin Kopit, Howard A. Burris III

Data analysis and interpretation: Alberto F. Sobrero, Joan Maurel, Manfred P. Lutz, M. Eugenia Vega-Villegas, Heinz-Josef Lenz, Christiane Langer, Justin Kopit, Howard A. Burris III

Manuscript writing: Alberto F. Sobrero, Joan Maurel, Manfred P. Lutz, Justin Kopit, Howard A. Burris III

Final approval of manuscript: Alberto F. Sobrero, Joan Maurel, Louis Fehrenbacher, Werner Scheithauer, Yousif A. Abubakr, Manfred P. Lutz, M. Eugenia Vega-Villegas, Cathy Eng, Jana Prausova, Heinz-Josef Lenz, Christophe Borg, Gary Middleton, Hendrick Kröning, Gabriele Luppi, Oliver Kisker, Angela Zubel, Christiane Langer, Justin Kopit, Howard A. Burris III

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Appendix

⇓

Fig A1.
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Fig A1.

Additional posthoc exploratory survival analyses: (A) restricted to the portion of the trial before regulatory approval of cetuximab; (B) nonrandomized comparison across patients in the irinotecan-only arm; (C) nonrandomized comparison across patients in the experimental arm. Subseq., subsequent.

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Footnotes

  • published online ahead of print at www.jco.org on April 7, 2008.

  • Sponsored by Merck KGaA, Bristol-Myers Squibb, and ImClone Systems.

  • Presented in part at the 41st Annual Meeting of the American Society of Clinical Oncology, Orlando, FL, June 2005; the 42nd Annual Meeting of the American Society of Clinical Oncology, Atlanta, GA, June 2006; safety and efficacy results from this study were presented at the Annual Meeting of the American Association for Cancer Research, April 14-18, 2007, Los Angeles, CA; and the quality of life results from this study were presented at the 43rd Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, June 2007.

  • Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

  • Received June 20, 2007.
  • Accepted January 8, 2008.
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  1. Published online before print April 7, 2008, doi: 10.1200/JCO.2007.13.1193 JCO vol. 26 no. 14 2311-2319
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