Japanese Journal of Clinical Oncology Advance Access published online on October 4, 2008
Japanese Journal of Clinical Oncology, doi:10.1093/jjco/hyn102
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© The Author (2008). Published by Oxford University Press. All rights reserved
Multicenter Phase II Study of Cetuximab Plus Irinotecan in Metastatic Colorectal Carcinoma Refractory to Irinotecan, Oxaliplatin and Fluoropyrimidines
1 Division of Digestive Endoscopy and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Chiba
2 Department of Medical Oncology, Faculty of Medicine, Oita University, Yufu, Oita
3 Division of Gastrointestinal Oncology, Shizuoka Cancer Center, Nagaizumi, Shizuoka
4 Department of Gastroenterology, Saitama Cancer Center Hospital, Ina-machi, Saitama
5 Department of Gastroenterology, Hokkaido University School of Medicine, Sapporo
6 Department of Diagnostic and Interventional Radiology, Aichi Cancer Center Hospital, Nagoya, Aichi
7 Department of Medical Oncology, Tochigi Cancer Center Hospital, Utsunomiya, Tochigi
8 Department of Medical Oncology, Ariake Cancer Institute Hospital, Tokyo
9 Department of Medical Oncology, Kinki University School of Medicine, Osakasayama, Osaka
10 Department of Gastroenterology, Osaka Medical College, Takatsuki, Osaka
11 Department of Medical Oncology, National Shikoku Cancer Center, Matsuyama, Ehime
12 Misawa Municipal Hospital, Misawa, Aomori, Japan
For reprints and all correspondence: Makoto Tahara, Division of Digestive Endoscopy and Gastrointestinal Oncology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba 277-8577, Japan. E-mail: matahara{at}east.ncc.go.jp
Received July 10, 2008; accepted September 1, 2008
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Abstract |
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 TOP Abstract INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONFundingAppendixAcknowledgementsReferences |
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Objective: Cetuximab is a chimeric IgG1 monoclonal antibody that specifically blocks the epidermal growth factor receptor. We evaluated the efficacy and safety of cetuximab in combination with irinotecan in patients with metastatic colorectal cancer (CRC) refractory to irinotecan, oxaliplatin and fluoropyrimidines.
Methods: Cetuximab was administered initially at a dose of 400 mg/m2 followed by weekly infusions at 250 mg/m2. Irinotecan was administered either weekly at a dose of 100 mg/m2 or every 2 weeks at 150 mg/m2.
Results: Between October 2005 and February 2006, 39 consecutive patients were enrolled. The response and disease control rates (complete or partial response, or stable disease) were 30.8% (95% CI, 17.0–47.6) and 64.1% (95% CI, 47.2–78.8), respectively. With a median follow-up of 14.4 months, median time to progression was 4.1 months (95% CI, 2.7–5.1) and median survival time was 8.8 months (95% CI, 5.9–12.8). Patients (5.1%) developed Grade 3 acne-like rash.
Conclusions: Combination therapy of cetuximab and irinotecan is effective and well-tolerated in patients with metastatic CRC refractory to irinotecan, oxaliplatin and fluoropyrimidines.
Key Words: cetuximab • irinotecan • colorectal cancer • multicenter phase II study
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INTRODUCTION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONFundingAppendixAcknowledgementsReferences |
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Colorectal cancer (CRC) is a major cause of morbidity and mortality worldwide (1). Palliative treatment of metastatic CRC is based on chemotherapy with 5-fluorouracil, irinotecan and oxaliplatin. Co-administration of these three drugs has substantially increased median overall survival (OS), from 12 months obtained several years ago to about 21–22 months today (2,3). Further, a recent meta-analysis of seven phase III trials in advanced CRC has shown that median OS is significantly correlated with the proportion of patients receiving all active agents during the disease course (4). Against this, however, treatment options for metastatic CRC patients with disease refractory to all three antitumor drugs are limited.
The addition of bevacizumab, a recombinant humanized monoclonal antibody, which targets vascular endothelial growth factor, to front- or second-line chemotherapy has improved progression-free survival (PFS) and OS (5). However, the clinical benefits of bevacizumab in third-line therapy have yet to be shown. In this regard, the National Comprehensive Cancer Network (NCCN) clinical practice guidelines (6,7) do not recommend bevacizumab as third-line therapy.
Cetuximab, a chimeric antibody of the IgG1 subclass, blocks the binding of the epidermal growth factor (EGF) and transforming growth factor alpha to the EGF receptor (EGFR) and inhibits ligand-induced activation of this receptor tyrosine kinase (8). Cetuximab has demonstrated antitumor activity in both in vivo and in vitro study (8). In addition, this agent not only enhanced the effects of irinotecan and radiotherapy (9) but also showed the ability to reverse resistance to irinotecan in preclinical studies (10).
Two previous studies have investigated the use of combination therapy of cetuximab plus irinotecan in subjects with irinotecan-refractory disease; the first, a single-arm Phase II trial, reported a response rate (RR) of 17% in 121 patients (11), the second, a randomized Phase II study of single agent cetuximab or cetuximab plus irinotecan, the BOND trial, reported a RR of 10.8% (111 subjects) versus 22.9% (218), respectively (12). Moreover, response in the combination arm in those who had received oxaliplatin was 22.2%. These results suggest that combination therapy of cetuximab plus irinotecan may benefit subjects refractory to irinotecan-based chemotherapy who have received oxaliplatin-based chemotherapies.
At the time the present study was undertaken, neither cetuximab nor bevacizumab was approved in Japan. Standard management of CRC instead consisted of the use of irinotecan, oxaliplatin or fluoropyrimidines, with no other standard options available after progression on these drugs. We therefore conducted a multicenter phase II study of cetuximab plus irinotecan in metastatic CRC refractory to irinotecan, oxaliplatin and fluoropyrimidines to evaluate the efficacy and safety of this combination.
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PATIENTS AND METHODS |
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Study Design and Patient Eligibility
The study was designed as a phase II, non-randomized, open-label, multicenter trial. Eligibility requirements included histologically confirmed, metastatic CRC that was surgically unresectable, as well as immunohistochemical evidence of EGFR expression measured semiquantitatively (>0 on a scale of 0, 1+, 2+ or 3+) at a single reference laboratory (SRL Medisearch, Inc.). Patients were required to have received irinotecan-based chemotherapy at a weekly irinotecan dose of
60 mg/m2 or every 2 weeks at 100 mg/m2, both defined as final doses, for at least 6 weeks or more. They were also required to have radiographically documented evidence of disease progression during this previous chemotherapy or within 3 months following the last dose of irinotecan. Further, patients were required to have received and failed fluoropyrimidine- and oxaliplatin-based chemotherapies. For this requirement, failure was defined as progression of disease (clinical or radiological) while receiving the previous oxaliplatin-based chemotherapy or within 6 months following the last treatment of an adjuvant therapy, or intolerance to the oxaliplatin-based chemotherapy. Regarding intolerance, this was defined as discontinuation due to allergic reaction, persistent neurotoxicity or delayed recovery from other toxicity that prevented re-treatment.
Other eligibility criteria included age 20 to less than 75 years, an Eastern Cooperative Oncology Group (ECOG) performance status (PS) score of 0–2, life expectancy of at least 2 months, and adequate organ function (absolute neutrophil count 1500/mm3, platelet count 100 000/mm3, hemoglobin 9 g/dl, aspartate aminotransferase and alanine aminotransferase 
2.5 times the upper limit of normal range, serum total bilirubin 1.5 times the upper limit of normal range and serum creatinine 1.5 mg/dl). Minimum treatment-free periods between the end of prior therapy and day of registration were 6 weeks for radiation therapy, 4 weeks for major surgery and 4 weeks for chemotherapy. At least one unidimensionally measurable target lesion by Response Evaluation Criteria in Solid Tumors (RECIST) criteria was required. Patients who previously received EGF signal transduction inhibitors or EGFR-targeting therapy were not eligible.
This protocol was reviewed and approved by the institutional review board of each participating center, and all patients gave written informed consent before participation.
Dosage and Drug Administration
The initial dose of cetuximab was administered as a single 2-h intravenous infusion at 400 mg/m2 followed by weekly 1-h infusions of 250 mg/m2. All patients were premedicated with an H1 histamine antagonist (e.g. diphenhydramine hydrochloride 50 mg po). Irinotecan was administered under the same schedule as the previous irinotecan-based therapy, namely either weekly at a dose of 100 mg/m2 on Days 1, 8, 15 and 22, repeated every 6 weeks; or every 2 weeks at 150 mg/m2 on Days 1, 15 and 29, repeated every 7 weeks.
Toxicity was graded according to the National Cancer Institute Common Toxicity Criteria (version 2.0.). If a patient experienced Grade 3 or worse skin toxicity, cetuximab therapy was withheld for up to two consecutive infusions with no subsequent change in dose level. If the toxicity resolved to Grade 2 or less by the following treatment period, treatment was resumed. With the second and third occurrences of Grade 3 or worse skin toxicity, cetuximab therapy was delayed again for up to two consecutive weeks with concomitant dose reductions to 200 and 150 mg/m2, respectively. Treatments were discontinued if more than two consecutive infusions were withheld or if there was a fourth occurrence of Grade 3 or worse skin toxicity. If a patient experienced a Grade 3 or worse hypersensitivity reaction, treatments were immediately discontinued. If a patient experienced a Grade 2 hypersensitivity reaction, cetuximab infusion was stopped, and if the reaction resolved to Grade 1 or less, it was resumed at half the previous infusion rate. Dose modification and treatment alterations for irinotecan were performed in accordance with hematological and non-hematological toxicities. If a patient experienced a Grade 4 thrombocytopenia or Grade 3 or worse neuropathy, irinotecan therapy was stopped. If a patient experienced a Grade 3 or worse febrile neutropenia, thrombocytopenia, or non-hematological toxicity, or Grade 4 neutropenia, irinotecan dose was reduced by one dose level.
Evaluation of Patients
Medical history, physical examination, laboratory test assessments and safety assessments were performed once before starting treatment and weekly thereafter. Chest X-ray was taken every 6 weeks.
Tumor measurement was performed within 4 weeks prior to starting administration of study therapy. Response was evaluated every 6 weeks thereafter according to the RECIST criteria. All responses were confirmed by an independent review committee.
Statistical Analysis
A sample size of 38 response-evaluable subjects was established based on expected and threshold RRs of 20 and 5%, respectively, under conditions of 
= 0.05 (one-tailed) if the RR was lower than the threshold RR, and β 0.1 if higher. The primary endpoint was the RR. If 38 subjects were response-evaluable, the null hypothesis would be rejected if at least five responses were observed. A patient who received at least one dose of study therapy was considered evaluable for response. Secondary endpoints, including duration of response and time to progression (TTP), were estimated using the Kaplan–Meier method.
TTP was defined as the period from the date treatment was started to the first observation of disease progression or to death from any cause before the confirmation of disease progression or after the most recent tumor assessment.
OS time was determined from the date of first administration of chemotherapy to the date of death or the last confirmation of survival. Duration of response was considered the period between the date of first confirmation of response and the date of documented disease progression, or the last confirmation of response. Comparisons among different subgroups of patients were performed using the log-rank test, and RR was the Fisher exact test. All analyses were conducted using SAS software (version 8; SAS Institute, Cary, NC, USA).
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RESULTS |
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Patient Characteristics
Forty-four of 46 centrally screened patients demonstrated detectable expression of EGFR. Of these 44, 39 consecutive patients were enrolled between October 2005 and February 2006. All patients received combination treatment with irinotecan and cetuximab. Patient characteristics are summarized in Table 1 and show a median age of 58 years, male predominance and good performance status. More than 60% (n = 25) of patients had received three or more regimens before entry.
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All patients had been refractory to irinotecan-based regimens and had received oxaliplatin and fluoropyrimidine before participation in the study. The median duration of prior irinotecan-based therapy was 24 weeks (range 6–52 weeks). Responses to irinotecan-based regimen were 2.6% complete response (CR), 23.1% partial response (PR), 41% stable disease (SD) and 30.8% progression of disease (PD). Median time from the last pre-study irinotecan dose to the initiation of cetuximab therapy was 7.2 months, with a range of 1.0–18.3 months. Thirty-five patients (89.7%) discontinued oxaliplatin-based regimens for disease progression, with a median of 2.1 months after last treatment. Response to the most recent oxaliplatin-based regimen was 0% CR, 5.1% PR, 46.2% SD and 46.2% PD.
Among other characteristics, 12 patients (30.8%) had received adjuvant chemotherapy; 34 (87.2%) had undergone surgical resection of the primary tumor; 20 (51.3%) had recurrent disease; and 19 (48.7%) had advanced disease. Two patients had received radiotherapy for CRC.
Efficacy
All patients enrolled were considered evaluable for efficacy (Table 2). An independent review committee determined that 12 patients (30.8%; 95% CI, 17.0–47.6) achieved PRs, and 25 (64.1%; 95% CI, 47.2–78.8) achieved either PRs or SDs (disease control). Median duration of response was 5.4 months (95% CI, 3.9–6.4), and median time to response was 1.4 months (range 1.3–5.3). Median TTP was 4.1 months (95% CI, 2.7–5.1) (Fig. 1). With a median follow-up of 14.4 months, the median OS was 8.8 months (95% CI, 5.9–12.8) (Fig. 2) (Table 2).
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No association with response was seen for either age, sex, performance status, number of prior chemotherapy regimens, primary tumor site or degree of EGFR immunostaining. In contrast, RR was significantly higher in patients who had achieved a response in a prior irinotecan regimen than in those who had not [(P = 0.04 Fisher exact test, 60.0% (95% CI, 26.2–87.8) versus 20.7% (95% CI, 10.2–48.4)]. Moreover, median OS of patients who had achieved a response in a prior irinotecan regimen was slightly longer than that of those who had not, albeit without significance (9.9 versus 8.8 months, P = 0.92; log-rank test).
The presence and severity of rash did not correlate with objective response (RR with Grade 0–1 versus Grade 2–3: 31.6 versus 30.0%, P = 0.73; Fisher exact test).
Adverse Events
Major adverse events are shown in Table 3. Overall, hematological toxicities were generally well tolerated, with Grade 3 or worse neutropenia observed in 23.1% of patients (n = 9). Febrile neutropenia was not observed. The incidence of Grade 3 or worse neutropenia was higher in patients receiving irinotecan every 2 weeks than in those on weekly regimens (27.6 versus 10.0%).
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Among other adverse events, non-hematological toxicities were also mild, with Grade 3 or worse diarrhea and anorexia observed in seven (17.9%) and six patients (15.4%), respectively. An acne-like rash, which is characteristic of treatment with cetuximab and other EGFR-targeted therapies and included acne, rash, dry skin, pruritus, acneiform dermatitis and papular rash, was observed in 38 patients (97.4%). Median time to the appearance of cetuximab-related acne-like rash was 7.0 days (range 1–31), while the median cumulative dose of cetuximab until appearance was 400 mg/m2 (range 400–1400) and duration of appearance was 121.5 days. Two patients (5.1%) experienced Grade 3 acne, with a duration of appearance of 10 and 15 days, respectively. All patients received topical treatment and 19 (51.4%) received oral antibiotic drugs, including minocycline. Median duration from the appearance of an acne-like rash to the start of antibiotic drugs, including topical treatment and minocycline, was 5.7 days. No patient experienced allergic reactions leading to the cessation of therapy. One patient discontinued treatment due to Grade 1 lung fibrosis, a condition that has never shown exacerbation without medication.
Duration of Treatment and Dose Intensity of Cetuximab and Irinotecan
The median duration of cetuximab treatment was 18 weeks (range 6–50 weeks), with a median of 16 infusions per patient (range 4–49 infusions). No patient required a dose reduction. Median dose intensity was 232 mg/m2 per week (range 150–254 mg/m2); 24 patients received doses at more than 90% of relative dose intensity, nine within 80–90% and six within 60–80%.
Fourteen patients (35.9%) required a dose reduction of irinotecan, primarily due to diarrhea (seven patients) and neutropenia (two patients). The median duration of treatment in all patients was 15 weeks (range 2–49), with a median of seven infusions per patient (range 2–30 infusions). Median dose intensity in all patients was 45 mg/m2 per week (range 25–61). According to the irinotecan schedule, it was 42 mg/m2 per week (range 25–59) in those receiving it weekly and 46 mg/m2 per week (range 29–61) in those receiving it every 2 weeks.
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DISCUSSION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONFundingAppendixAcknowledgementsReferences |
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In this multicenter Phase II study of metastatic CRC, the combination of cetuximab plus irinotecan showed substantial efficacy as third-line treatment in patients failing previous irinotecan-, oxaliplatin- and fluoropyrimidine-based chemotherapy.
The present study was based on a Phase I study in Japan of single-agent cetuximab in subjects with solid tumors in whom standard therapy had failed (13). In that study, no DLTs and good tolerance were observed at the recommended dose, which was obtained from previous Phase II studies in Western countries. Further, the safety data for cetuximab did not obviously differ from those in Western patients and the pharmacokinetic profile was comparable. Further, another study demonstrated a lack of drug–drug interactions between cetuximab and irinotecan, and the absence of any contribution of one to the safety profiles of the other (14).
On these bases, we selected the same doses as those used overseas as the recommended dose of cetuximab in this Phase II study, namely 400 mg/m2 initial dose and 250 mg/m2 weekly thereafter. The incidence of Grade 3 or worse acne was 5.1%, which was lower than the 9.4–29.1% range in previous studies, whereas the incidence and severity of other non-hematological toxicities were comparable. No patients experienced Grade 3 or worse infusion reactions despite the use of antihistamines only as premedication. In a large multinational Phase II study, combination with corticosteroids and antihistamines reduced the incidence of severe infusion reactions compared with the effect with antihistamines only (15). Although the incidence of Grade 3 or worse neutropenia was higher in patients receiving irinotecan every 2 weeks than in those receiving it weekly (27.6 versus 10.0%), no febrile neutropenia or life-threatening adverse events were observed in any patient. These results indicate that the combination of cetuximab and irinotecan is well-tolerated in Japanese patients with metastatic CRC refractory to irinotecan, oxaliplatin and fluoropyrimidines.
Several recent clinical trials of single-agent cetuximab in CRC refractory to irinotecan have shown similar objective RR, disease control rates, median TTP and median OS, with ranges from 8 to 12%, 32 to 50%, 1.4 to 4.2 months and 6.4 to 7.0 months, respectively (12,16–18). A more recent randomized Phase III trial of cetuximab plus best supportive care (BSC) versus BSC alone in patients with pre-treated metastatic EGFR-expressing CRC (NCIC CTG CO.17) demonstrated a significantly prolonged PFS and OS with cetuximab compared with BSC alone, indicating that cetuximab is the first targeted therapy to show a survival benefit as a single agent in metastatic CRC (17).
Moreover, the combination of cetuximab plus irinotecan has been evaluated in clinical trials in patients with previously treated metastatic CRC, including one randomized and three non-randomized trials (11,12,15,19). These studies showed a similar objective RR, disease control rate, median TTP and median OS, ranging from 17 to 25.4%, 55.5 to 63.6%, 4.1 to 4.7 months and 8.6 to 9.8 months, respectively.
Here, we showed an RR of 30.8% and a disease control rate of 64.1%. Moreover, median TTP was 4.1 months, median OS was 8.8 months and median duration of response was 5.4 months. These results indicate that combination therapy with cetuximab and irinotecan produced notable antitumor activity in metastatic CRC patients who had been pretreated with irinotecan, oxaliplatin and fluoropyrimidine, confirming the results of previous studies (11,12,15,19).
With regard to first-line treatment of metastatic CRC, a Phase II trial of cetuximab in combination with fluorouracil, leucovorin and oxaliplatin (FOLFOX-4) reported the encouraging RR of 72%, median PFS of 12.3 months and median OS of 30.0 months (20). Further, a randomized trial of FOLFIRI with or without cetuximab (the CRYSTAL trial) demonstrated a statistically significant higher overall RR (46.9 versus 38.7%, P = 0.0038), longer median PFS (8.9 versus 8.0 months, P = 0.0479) and higher surgical resection rate after chemotherapy (2.5 versus 6.0%) for the cetuximab combination arm (21). Further studies in these first- or second-line settings are required.
Among other results, we found that the RR of patients who had achieved a response in a prior irinotecan regimen was significantly higher than that of patients who had not, though the difference in survival was not significant. This result suggests that cetuximab reversed resistance to irinotecan and thereby enhanced its antitumor activity. Although this combination showed sufficient antitumor activity as third-line treatment in patients who had not achieved a prior response to irinotecan, greater clinical benefit would be obtained in those who had. Among previous studies, while the BOND study reported a subgroup analysis by progression during or within 4 weeks after pre-study with irinotecan, no study has reported a subgroup analysis by response to a prior regimen (12). The small number of patients notwithstanding, our present study is the first clinical trial of cetuximab and irinotecan for metastatic CRC to conduct a subgroup analysis by response to a prior irinotecan regimen.
Interestingly, we saw no correlation between response and the degree of EGFR expression by immunohistochemistry (IHC). Previous studies showed that EGFR expression detected by IHC was not a consistent predictor of response to EGFR-targeted therapy, and that EGFR-non-detectable patients also achieved a response to EGFR-targeted therapy (12,16). Proposed explanations for this lack of a consistent correlation include inaccuracies linked to IHC testing resulting from potential sample degradation or epitope loss during fixation. On the basis of these findings, the NCCN considers that the evaluation of EGFR expression by IHC is not of predictive value in the determination of indications for anti-EGFR monoclonal antibody therapy (6).
With regard to adverse findings, a number of studies have demonstrated that the presence and severity of rash strongly correlate with efficacy (12,17). Here, in contrast, the presence and severity of rash were not correlated with clinical benefit. The incidence of grade 3 acne-like rash was lower than in previous studies. One reason for this lack of correlation between the presence and severity of rash and clinical benefit might be our early administration of antibiotics prior to the development of grade 3 acne-like rash. A recent randomized double-blind trial of prophylactic oral minocycline and topical tazarotene for cetuximab-associated acne-like eruption demonstrated that oral minocycline might be useful in decreasing the severity of the acneiform rash during the first month of cetuximab treatment (22). In the present study, all patients received topical agents and 51.4% received oral antibiotic drugs, including minocycline, after doctors diagnosed skin rash; median duration from the start of antibiotics to the appearance of acne-like rash was 5.7 days, which might have reduced severity.
Recent findings have confirmed an association between the expression of EGFR amplification and K-ras mutation and the efficacy to cetuximab therapy (23). Further, K-ras mutation has been shown to be an independent prognostic factor in CRC patients treated with cetuximab (24,25). While the expression of these variables was not analyzed in the present study, these findings will likely assist in future efforts to define the subpopulation of patients most likely to benefit from cetuximab.
In conclusion, this study provides evidence of the substantial clinical efficacy of combination therapy with cetuximab plus irinotecan as third-line treatment in metastatic CRC patients who are refractory to irinotecan-based chemotherapy and who have failed oxaliplatin- and fluoropyrimidine-based chemotherapies in their previous treatment.
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Funding |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONFundingAppendixAcknowledgementsReferences |
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Bristol-Myers K.K. and Merck Serono Co., Ltd.
Conflict of interest statement
None declared.
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Appendix |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONFundingAppendixAcknowledgementsReferences |
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Additional authors and affiliations:
Keiko Asai1, Hideyuki Hashiba2
1Bristol-Myers K.K. Shinjuku i-Land Tower 5-1, Nishi-Shinjuku 6-chome, Tokyo 163-1328, Japan and 2Merck Serono Co., Ltd, 6F Meguro Tokyu Bldg., 2-13-17 Kamiosaki, Tokyo 141-0021, Japan.
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Acknowledgements |
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The authors would like to thank the patients and families who participated in this study, their colleagues at many centers involved.
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References |
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