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Journal of Clinical Oncology, Vol 25, No 33 (November 20), 2007: pp. 5225-5232 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.13.2183 Phase II Trial of Cetuximab in Combination With Fluorouracil, Leucovorin, and Oxaliplatin in the First-Line Treatment of Metastatic Colorectal Cancer
From Medical Oncology Service, Vall d'Hebron University Hospital, Barcelona; Servicio de Oncología Médica, Hospital Clínico San Carlos, Madrid; Servicio de Onco-Hematología, Hospital Clínico Universidad de Valencia, Valencia, Spain; University Hospital Gasthuisberg, Leuven; Université Catholique de Louvain, Cliniques Universitaires St Luc; Hôpital Universitaire Erasme, Brussels, Belgium; Hôpital Tenon; Medical Oncology Service, Hospital Saint-Antoine; Centre Paul Papin, Angers, France; Medical Oncology Service, University of Naples "Federico II"; Medical Oncology Service, Second University of Naples, Naples, Italy; and Medical Sciences Oncology, Merck KGaA, Darmstadt, Germany Address reprint requests to Josep Tabernero, MD, Medical Oncology Department, Vall d'Hebron University Hospital, P. Vall d'Hebron, 119-129, 08035 Barcelona, Spain; e-mail: jtabernero{at}vhebron.net
Purpose This phase II study investigated the efficacy and safety of cetuximab combined with standard oxaliplatin-based chemotherapy (infusional fluorouracil, leucovorin, and oxaliplatin [FOLFOX-4]) in the first-line treatment of epidermal growth factor receptor–expressing metastatic colorectal cancer (mCRC). Patients and Methods The activity of cetuximab plus oxaliplatin was investigated in colon cancer cell lines and xenograft models. In the clinical study, patients with mCRC received on day 1 of a 14 day cycle, cetuximab (initial dose 400 mg/m2 during week 1, then 250 mg/m2 weekly) followed by FOLFOX-4 (oxaliplatin 85 mg/m2 on day 1; leucovorin 200 mg/m2 on days 1 and 2, followed by fluorouracil 400 mg/m2 bolus then 600 mg/m2 intravenous infusion during 22 hours on days 1 and 2). Results The preclinical studies confirmed the supra-additive activity of cetuximab to oxaliplatin. In the clinical study, 43 patients were included, with a median age of 65 years (range, 43 to 78 years). Response rates (RRs) were 79% (unconfirmed) and 72% (confirmed), with 95% disease control. Median progression-free survival (mPFS) and median duration of response were 12.3 and 10.8 months, respectively. Ten patients (23%) underwent resection with curative intent of previously unresectable metastases. After a median follow-up of 30.5 months, median overall survival (mOS) was 30.0 months. Cetuximab did not increase the characteristic toxicity of FOLFOX-4 and was generally well tolerated. Conclusion Cetuximab in combination with FOLFOX-4 is a highly active first-line treatment for mCRC, showing encouraging RR, mPFS, and mOS values. The treatment resulted in a high resectability rate, which could potentially result in an improved cure rate. This combination is under phase III development.
In Europe, colorectal cancer (CRC) was estimated to be the second most frequent cause of cancer-related death in 2006.1 Although there have been substantive advances in the treatment of metastatic CRC (mCRC), median survival remains less than 2 years and less than 5% of patients survive for more than 5 years.2-7 However, as originally demonstrated in the retrospective analysis of Giacchetti et al,8 chemotherapy can render previously unresectable liver metastases operable, conferring the possibility of curative surgery. Additional improvements in treatment are likely to be facilitated by the use of rationally selected therapeutic agents that target functionally important proteins in tumor cells, such as the epidermal growth factor receptor (EGFR), expressed in 75% to 89% of CRCs.9-13 Cetuximab (Erbitux; Merck KGaA, Darmstadt, Germany), an immunoglobulin G1 monoclonal antibody, specifically targets EGFR with a higher affinity than its natural ligands.14 Cetuximab prevents EGFR from binding to these endogenous ligands and therefore from adopting the extended configuration necessary for dimerization and signal transduction.15 Monoclonal antibody binding also stimulates receptor internalization and degradation.16,17 In preclinical models, cetuximab has been shown to increase tumor cell apoptosis,18-20 suppress invasion and metastasis,21 inhibit proliferation,22 and downregulate the production of proangiogenic factors.23 Cetuximab has demonstrated clear activity, both as a single agent and when combined with irinotecan, in mCRC patients who have experienced treatment failure after irinotecan-based therapy.11,12,24,25 Furthermore, the combination of cetuximab with different irinotecan, fluorouracil (FU), and leucovorin (LV) regimens has shown an acceptable safety profile and promising response rates (43% to 67%) in the first-line setting.13,26,27 First-line regimens combining either irinotecan or oxaliplatin with infusional FU/LV seem to be essentially equivalent in terms of efficacy.28-30 However, the available published data suggest that the use of oxaliplatin combined with infusional FU/LV may produce greater shrinkage of metastatic sites.30 This phase II study was designed to evaluate the safety and efficacy of the combination of cetuximab plus oxaliplatin, FU, and LV (FOLFOX-4) as a first-line treatment for patients with mCRC. A preclinical study was conducted to elucidate further the rationale for the combination of cetuximab and oxaliplatin.
Preclinical Investigations In vitro experiments. GEO, SW480, and Caco2 human colon cancer cell lines were maintained in culture as described previously.31 Cell suspensions were layered over 0.5 mL of a 0.8% (soft) agar-medium base layer in 24-multiwell cluster dishes (Becton Dickinson, Lincoln Park, NJ) and treated with different concentrations of oxaliplatin and/or cetuximab. After 10 to 14 days, cells were stained with nitro blue tetrazolium (Sigma Chemical Co, St Louis, MO) and colonies larger than 0.05 mm were counted.31 The results of the combined treatment with oxaliplatin and cetuximab were analyzed according to Chou and Talalay,32,33 using the CalcuSyn software program (Biosoft, Cambridge, United Kingdom). The resulting combination index (CoI) is a quantitative measure of the degree of interaction between different drugs: CoI = 1, additivity; CoI more than 1, antagonism; CoI between 1 and 0.7, slight synergism; CoI between 0.7 and 0.3, synergism; and CoI less than 0.3, strong synergism.
Tumor xenografts in nude mice.
Four- to 6-week-old female BALB/c athymic (nu+/nu+) mice were injected subcutaneously with 1 x 107 GEO cells that had been resuspended in 200 µL of Matrigel (Becton Dickinson). After 7 days, when established tumors of approximately 0.2 to 0.3 cm3 diameter were detected, mice were treated intraperitoneally with oxaliplatin (15 mg/kg/mouse on days 1 of each week for 3 weeks), and/or intraperitoneally with cetuximab (1 mg/mouse on days 2 and 5 of each week for 3 weeks). Each group included 10 mice. Tumor volume was measured using the formula
Clinical Investigations: Patient Eligibility
Trial Design The primary end point was best overall (confirmed) response using the modified WHO criteria. RECIST criteria were applied subsequently to assess and confirm overall response.34 Radiologic assessment of response was carried out at the end of the fourth and sixth cycles and then every six cycles until the end of the study, and if progressive disease (PD) had not been observed, subsequently every 12 weeks, as per routine clinical practice. Secondary end points included progression-free survival time (PFS), duration of response (DOR), overall survival (OS), and the safety of the combination.
Statistical Methods and Considerations All adverse events (AEs) reported with onset on or after the first dosing day of study medication and captured up to 6 weeks after the end of the last cetuximab infusion were summarized by worst severity per patient according to the National Cancer Institute Common Toxicity Criteria version 2.0. With an assumed response rate of 50%, a sample size of 40 patients was considered sufficient to observe at least 15 responders with a probability of 90%. All efficacy and safety analyses were evaluated at a purely exploratory level. Considering that 7% of patients might not be assessable for tumor response, 43 patients were enrolled to fulfill the target requirement of 40 patients.
Cetuximab and Oxaliplatin in Preclinical Models A synergistic growth inhibition was observed with oxaliplatin and cetuximab (Fig 1). The CoI values ranged between 0.10 and 0.40, suggesting that in the tested cancer cell lines, the synergism in soft agar colony formation inhibition was strong. Experiments were performed in triplicate. In the GEO colon cancer subcutaneous xenografts (Fig 2), a 60% inhibition of tumor growth was obtained with oxaliplatin or cetuximab single-agent treatment at the end of 3 weeks of therapy. However, this effect was reversible on cessation of treatment, given that GEO tumors resumed a growth rate similar to that observed in control untreated mice within 1 to 3 weeks. In contrast, an approximately 90% prolonged tumor growth inhibition resulted from the combination of oxaliplatin and cetuximab, resulting in three of 10 mice considered cured because they had no histologic evidence of tumor at the end of the observation period (56 days after GEO tumor cell injection). In the remaining seven animals, tumor size at this time point was similar to that of day 7. t test, used to compare tumor sizes among different treatment groups at day 28 after GEO cell injection, showed statistically significant differences for cetuximab versus control (two-sided P < .01), oxaliplatin versus control (two-sided P < .01), oxaliplatin plus cetuximab versus control (two-sided P < .001), oxaliplatin plus cetuximab versus oxaliplatin (two-sided P < .01), and oxaliplatin plus cetuximab versus cetuximab (two-sided P < .01).
Clinical Study: Patient Demographics Sixty-two mCRC patients were screened, 52 (84%) demonstrated tumor EGFR expression, and 43 were subsequently enrolled onto the study. All 43 patients (intention-to-treat and safety population) were assessable for safety, with 42 assessable for response. Baseline patient and disease characteristics are summarized in Table 1. Twenty patients (47%) had metastatic lesions in one organ and 23 patients (53%) had metastatic lesions in more than one organ. As expected, hepatic metastases were the most common, with lesions detected in 37 patients (86%). However, only 17 patients (40%) had metastases confined exclusively to the liver.
Treatment Compliance Treatment exposure is summarized in Table 2. The median duration of cetuximab treatment was 31 weeks, with 70% of patients achieving a relative dose intensity  80%. The majority of patients (35 patients; 81%) experienced cetuximab treatment delays, which were 9 days in 20 patients (46%). The most common reason for cetuximab dose delay was the occurrence of an AE (31 patients; 72%); skin tissue toxicities (20 patients; 47%) were the most frequent cause. Overall, only six patients (14%) required cetuximab dose reductions. The median duration of both oxaliplatin and FU treatment was 28 weeks. Eight patients (19%) continued cetuximab monotherapy after discontinuation of FOLFOX-4, for a median of 16.2 weeks (range, 1 to 51 weeks). Oxaliplatin was delayed in 36 patients (84%) and FU was delayed in 38 patients (88%). Delays were 9 days in 28 patients (65%) and 34 patients (79%), respectively. Dose reductions of oxaliplatin (18 patients; 42%) and FU (25 patients; 58%) were more common than for cetuximab. Although the numbers of patients experiencing chemotherapy or cetuximab treatment delays were comparable, these delays tended to be more extensive for the two cytotoxic agents compared with those reported for cetuximab.
Efficacy Efficacy data are summarized in Table 3. Forty-two patients were considered assessable for response (one patient withdrew consent after the first dose of study treatment). The results are presented for all 43 patients in the intention-to-treat population. Thirty-four objective responses were observed (four CRs and 30 PRs), yielding an overall response rate of 79%. Thirty-one responses (four CRs and 27 PRs) were confirmed subsequently, to provide a best overall confirmed response rate of 72%. In three patients, responses could not be confirmed for reasons unrelated to disease progression: one patient underwent surgery for a metastasis before the confirmation and two patients withdrew from treatment before confirmation and started new therapies. These three patients were therefore assessed as having a PR in the context of the unconfirmed response rate, but as having stable disease with respect to the calculation of the confirmed response rate.
Median PFS was 12.3 months (95% CI, 7.7 to 15.8 months) with a median DOR of 10.8 months (95% CI, 7.1 to 13.9 months; Fig 3A). Overall, PFS time was censored in 27 patients, including five patients receiving ongoing treatment at data cutoff, five patients each for reasons related to surgery of metastases and for withdrawal of consent, three patients each for CR and adverse events, and six patients for other reasons. After a median follow-up of 30.5 months, the median OS was 30.0 months (95% CI, 17.8 to 33.8), with 49% of patients still alive and OS time censored at the cutoff date (Fig 3B). One- and 2-year survival rates were 70% and 53%, respectively. Twenty-two patients (51%) received additional chemotherapy after the end of the study, 18 (42%) of whom received irinotecan-based therapy. Ten patients (23%) whose metastases were initially assessed as inoperable were rendered resectable by the treatment regimen (Table 3). These 10 patients, with disseminated disease in the liver (eight patients), lung (one patient), or adrenal gland (one patient), subsequently underwent potentially curative surgery. Nine patients (21%) had no evidence of residual disease (R0) after resection. Although the interruption of treatment to perform surgery was allowed in the protocol, three patients elected to leave the study at this point.
Safety Sixteen patients had died at the time of the main analysis (April 1, 2005), 15 as a result of PD and one a result of an intercurrent illness (pneumonia). There were no treatment-related deaths. Grade 3/4 AEs were reported for 91% of patients, of which 56% were believed to be related to cetuximab treatment. Treatment was discontinued due to AEs in 21 (49%) patients. Cetuximab only and chemotherapy only were discontinued in three (7%) and 12 (28%) patients, respectively, with six patients (14%) discontinuing both. The most frequent reasons for discontinuing cetuximab treatment were skin-related AEs in four patients (9%) followed by pneumonia (two patients; 5%). The most frequent reason for discontinuing chemotherapy was oxaliplatin-related neurotoxicity, with peripheral sensitive nervous system disorders causing treatment cessation in 10 patients (23%). The most commonly reported grade 3/4 AEs (Table 4) were diarrhea (11 patients), neutropenia (10 patients), and paresthesia (eight patients). The most frequently observed skin reaction in the current study was rash, which was seen in 23 patients (53%; grade 3 in seven patients; 16%). Other common adverse effects (all grades) associated with cetuximab treatment, such as dry skin (19 patients; 44%), conjunctivitis (15 patients; 35%), skin fissures (14 patients; 33%), and paronychia (12 patients; 28%) were also observed.
This phase II study was primarily designed to evaluate the response rate of FOLFOX-4 combined with cetuximab in the first-line treatment of patients with EGFR-expressing mCRC. The confirmed best overall response rate of 72% achieved in this study compares favorably with rates of 45% and 51% reported for FOLFOX-4 alone.5,38 In addition, 23% of patients maintained stable disease for at least 3 months. The preliminary data from two randomized studies evaluating the combination of cetuximab and FOLFOX have been reported recently. The redesigned randomized phase II CALGB 80203 study achieved a response rate of 60% in 58 patients receiving this combination.39 The large, randomized, phase II Oxaliplatin and Cetuximab in First-Line Treatment of mCRC (OPUS) trial showed a 46% response rate in 169 patients treated with cetuximab plus FOLFOX-4.40 Although the response rate for the combination in the OPUS study appears less than that reported in the other studies, the 36% response rate in the control arm is also less than the value generally reported for FOLFOX-4. Therefore, the apparent cross-study variability in response rates may be due to some extent to patient selection for small phase II studies compared with larger randomized studies that recruit essentially unselected patients. It should also be noted that a relatively high fraction of patients in the current study had a low disease burden, with 47% having only a single distant metastatic site—a factor that may have contributed to the high response rate. Similarly, with a median PFS of 12.3 months and a median OS of 30 months, the survival figures in this study are among the best reported in the literature for mCRC.5,30,38 It is conceivable that the long interval between radiologic assessments (12 weeks) may have contributed to the long median PFS and DOR times achieved; however, the corresponding median OS figure suggests that this was unlikely to be a significant factor in this case. The clinical activity of this combination is supported by the ancillary preclinical study reported here (which demonstrated strong synergism of cetuximab and oxaliplatin, as well as prolonged inhibition of tumor growth), and also by the work of Prewett et al41 in both oxaliplatin-sensitive and oxaliplatin-resistant CRC cell lines. Taken together, these preclinical and clinical data strongly suggest that cetuximab combined with FOLFOX-4 is active in the first-line treatment of mCRC. Of note is that this is now the third study in mCRC patients to report promising results for overall survival for a first-line cetuximab combination regimen.13,42 Folprecht reported that in studies including nonselected mCRC patients (those with hepatic and/or extrahepatic metastatic disease), as is the case for our study, the hepatic resection rate was in the 1% to 26% range.43 The resection with curative intent rate of 23% (10 of 43 patients; eight of 43 [19%] with hepatic metastases) achieved in the current study is therefore comparable to the highest reported for unselected patients.43,44 This suggests that the use of cetuximab combined with cytotoxic therapy early in a patient's treatment course could perhaps render a higher fraction of mCRC fully resectable, an assertion supported by the significantly higher R0 resection rate reported for the cetuximab plus fluorouracil, leucovorin, and irinotecan arm of the Cetuximab Combined With Irinotecan in First-Line Therapy for Metastatic Colorectal Cancer (CRYSTAL) study.45 Although most of the patients (91%) experienced a grade 3/4 AE, the combination of cetuximab and FOLFOX-4 was generally well tolerated, and there was no evidence suggesting that cetuximab increased the frequency or severity of the characteristic toxicities associated with FOLFOX. The typical and manageable EGFR-inhibitor–related adverse effects, rash and acne, were reported at grade 3/4 for 16% and 14% of patients, respectively. It is particularly important to emphasize that the population included in this study was older than the average mCRC trial population, with a median age of 65 years, with more than 25% of the patients older than 70 years. Despite this factor, the toxicity profile was manageable. In conclusion, this study suggests that cetuximab in combination with FOLFOX-4 is safe and active in the first-line treatment of mCRC. The regimen has the potential to significantly improve resection rates in advanced disease, which may in turn result in increased survival. Study data are consistent with the hypothesis that the efficacy of cetuximab is not agent specific, and provide a rational basis for additional development. Randomized phase II/III trials are mandated and necessary to evaluate more fully the role of cetuximab, oxaliplatin, and fluoropyrimidine combinations in the treatment of mCRC. This requirement will be addressed in unselected populations of patients with mCRC in the ongoing European COIN and NORDIC-VII studies, the US Cancer and Leukemia Group B 80405 study, and in the selected patient populations with unresectable liver metastases in the Tratamiento de Tumores Digestivos (TTD) and Cetuximab in Neoadjuvant Treatment of Non-resectable Colorectal Liver Metastases (CELIM) studies.
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) Consultant or Advisory Role: Josep Tabernero, Merck KGaA (C), Sanofi-aventis (C); Eric Van Cutsem, Merck KGaA (C); Eduardo Díaz-Rubio, Merck KGaA (C), Sanofi-aventis (C); Aimery de Gramont, Sanofi-aventis (C) Stock Ownership: None Honoraria: Josep Tabernero, Merck KGaA, Sanofi-aventis; Andrés Cervantes, Merck KGaA, Sanofi-aventis; Thierry André, Merck KGaA; Aimery de Gramont, Sanofi-aventis Research Funding: Josep Tabernero, Merck KGaA, Sanofi-aventis; Eric Van Cutsem, Merck KGaA, Sanofi-aventis; Eduardo Díaz-Rubio, Sanofi-aventis Expert Testimony: None Other Remuneration: None
Conception and design: Josep Tabernero, Eric Van Cutsem, Eduardo Díaz-Rubio, Aimery de Gramont Financial support: Oliver Kisker Administrative support: Oliver Kisker Provision of study materials or patients: Josep Tabernero, Eric Van Cutsem, Eduardo Díaz-Rubio, Andrés Cervantes, Yves Humblet, Thierry André, Jean-Luc Van Laethem, Patrick Soulié, Esther Casado, Chris Verslype, Javier Sastre Valera, Giampaolo Tortora, Fortunato Ciardiello, Aimery de Gramont Collection and assembly of data: Josep Tabernero, Eric Van Cutsem, Andrés Cervantes, Yves Humblet, Chris Verslype, Javier Sastre Valera, Aimery de Gramont Data analysis and interpretation: Josep Tabernero, Eric Van Cutsem, Oliver Kisker Manuscript writing: Josep Tabernero, Eric Van Cutsem, Eduardo Díaz-Rubio, Giampaolo Tortora, Fortunato Ciardiello, Aimery de Gramont Final approval of manuscript: Josep Tabernero, Eric Van Cutsem, Eduardo Díaz-Rubio, Andrés Cervantes, Yves Humblet, Thierry André, Jean-Luc Van Laethem, Patrick Soulié, Esther Casado, Chris Verslype, Javier Sastre Valera, Giampaolo Tortora, Fortunato Ciardiello, Oliver Kisker, Aimery de Gramont
We thank the enrolled patients and the clinicians who contributed to their care; and the following Merck KGaA personnel: Neus Gascon, Jordi Farres, Angela Zubel, Anja H. Loos, Stefan Wagner, Silvia Corretge, and Margaret Ebmeier-Egg.
Presented in part at the 40th Annual Meeting of the American Society of Clinical Oncology, June 5-8, 2004, New Orleans, LA; at the 29th Meeting of the European Society for Medical Oncology, October 29-November 2, 2004, Vienna, Austria; at the 41st Annual Meeting of the American Society of Clinical Oncology, May 13-17, 2005, Orlando, FL; at the 13th European Cancer Conference, October 30-November 3, 2005, Paris, France; and at the American Society of Clinical Oncology Gastrointestinal Symposium, January 19-21, 2007, Orlando, FL. Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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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
/6 x larger diameter x (smaller diameter)2. 
2 (or for those > 75 years, a performance status of 0); and adequate hepatic, renal, and bone marrow functions. Patients were ineligible if they had a history of previous exposure to EGFR-targeted therapy, previous chemotherapy for mCRC, or uncontrolled severe organ/metabolic dysfunction. The study was conducted in accordance with the Declaration of Helsinki and all patients provided written, informed consent. Patients were enrolled between June 30, 2003, and December 17, 2003. The cutoff date for the main analysis was April 1, 2005 (five patients remained under treatment at that time). This was extended for the evaluation of overall survival to June 30, 2006. 
