Annals of Oncology Advance Access originally published online on December 10, 2007
Annals of Oncology 2008 19(4):711-716; doi:10.1093/annonc/mdm516
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gastrointestinal tumors |
First-line single-agent cetuximab in patients with advanced colorectal cancer
1 Medical Oncology Unit, Ospedale S. Martino, Genoa
2 Oncologia Falck Unit, Ospedale Niguarda Ca’ Granda, Milan, Italy
* Correspondence to: Prof. A. Sobrero, Medical Oncology Unit, Ospedale S. Martino, Largo R. Benzi 10, 16132 Genoa, Italy. Tel: +39-10-5553301; Fax: +39-10-5555139; E-mail: alberto.sobrero{at}hsanmartino.it
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Abstract |
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Background: The anti-epidermal growth factor receptor (EGFR) antibody cetuximab is active in heavily pretreated patients with metastatic colorectal cancer (mCRC) both in monotherapy and in combination with chemotherapy (CT). This study assesses the antitumor activity of single-agent cetuximab in CT-naive patients.
Patients and methods: Phase II clinical trial was used. Patients were EGFR positive by immunohistochemistry and were not candidate for radical surgery, even in the case of substantial tumor shrinkage. Cetuximab was administered weekly.
Results: Thirty-nine patients were treated and evaluated. The most common adverse event was skin toxicity (89% any grade; 48% grade 1; 31% grade 2; 10% grade 3). One patient had a complete response and three obtained partial responses (10% overall response rate). Thirteen patients had stable disease (34%). Twenty-two patients experienced progressive disease (56%). Overall median time to progression (TTP) was 2 months, and the responders individual TTP was 12, 9, 9, and 6 months.
Conclusions: Even in chemo-naive patients, cetuximab as single agent is active only in a small fraction of mCRC, similarly to what has been reported for heavily pretreated patients. The extent of benefit when response occurs is, however, such that it is mandatory to intensify the search for the predictive markers of response to cetuximab therapy.
Key words: biological therapy, cetuximab, colorectal cancer
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introduction |
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TopAbstractintroductionpatients and methodsresultsdiscussionfundingAcknowledgementsReferences |
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Chemotherapy (CT) is the mainstay of the treatment of metastatic colorectal cancer (mCRC), and, except for a minority of patients still candidate for salvage surgery, the goal of CT is palliation. Since the introduction of 5-fluorouracil (5-FU), CT has proved to prolong median survival time (MST) of patients with advanced disease. With optimal scheduling, 5-FU doubled MST compared with best supportive care alone [1, 2]. Recent advances in combination CT, by addition of either oxaliplatin or irinotecan to 5-FU, resulted in improvement in both response rate (RR) and overall survival [3], with maximal benefit obtained when patients receive all the three agents during the course of their disease [4]. Moreover, combination CT has improved the possibility to downstage metastatic patients, thereby making resectable an additional 12%–20% of patients initially considered unresectable [5]. Five-year survival rates in patients undergoing liver metastasis resection are significantly higher than those of nonsurgical patients, reaching 30%–35% rate, with median values ranging from 33 to 46 months [6].
When the disease is, however, disseminated to more than one organ, it is no longer amenable to cure and the only therapeutic option is palliative CT. In these conditions, one may consider whether ‘less aggressive’ approaches may lead to equivalent clinical benefit of the classical approach with CT doublets. Along these lines, three different approaches have addressed this point:
- a) Delaying the onset of CT in asymptomatic patients—the impact of early onset of palliative CT on survival of patients with advanced colorectal cancer (CRC) is still a matter of debate. While the Nordic study showed a survival benefit in mCRC patients treated early with CT [7], a meta-analysis of two randomized trials (Australasian and Canadian) indicated equivalent survival rates in asymptomatic patients who received early treatment compared with those whose treatment was delayed until the onset of symptoms (median delay 5 months) [8].
- b) Introducing pauses between cycles of CT—randomized trials have tested continuous CT until progression versus intermittent therapy, i.e. stopping CT after few cycles and restarting the same regimen at disease progression [9, 10] or after a defined period of time [11]. Two trials have demonstrated no significant difference in survival rates in advanced CRC patients treated either with continuous or with intermittent CT [9, 11]. Of relevance, patients on intermittent CT experienced significantly fewer toxic effects than those in the continuous CT arms. Recent update of OPTIMOX2 study, however, showed a better outcome for patients in the continuous treatment arm [10], thus making the issue of intermittent CT still controversial.
- c) Sequential therapies—recent trials have been designed to test the efficacy of a less aggressive single-agent regimen (5-FU) followed by combination CT versus combination regimens up front [12, 13]. Preliminary results show noninferiority of the sequential approach, thereby providing an additional therapeutic option to individualized treatment on the basis of patient characteristics.
- b) Introducing pauses between cycles of CT—randomized trials have tested continuous CT until progression versus intermittent therapy, i.e. stopping CT after few cycles and restarting the same regimen at disease progression [9, 10] or after a defined period of time [11]. Two trials have demonstrated no significant difference in survival rates in advanced CRC patients treated either with continuous or with intermittent CT [9, 11]. Of relevance, patients on intermittent CT experienced significantly fewer toxic effects than those in the continuous CT arms. Recent update of OPTIMOX2 study, however, showed a better outcome for patients in the continuous treatment arm [10], thus making the issue of intermittent CT still controversial.
The availability of targeted therapies in clinical practice has further increased the therapeutic options for mCRC. In particular, cetuximab, a human/murine chimeric immunoglobulin G1 mAb directed to the epidermal growth factor receptor (EGFR)-binding site, has recently demonstrated to be active in chemorefractory mCRC patients both in combination with irinotecan [14] and in monotherapy [14–17], achieving 23% and 11% overall RR, respectively.
Whereas cetuximab has a clear indication in the salvage setting [14–17], its role in first-line therapy remains investigational. After a series of very promising phase II trials of cetuximab plus CT as first-line treatment, large randomized trials of CT regimens incorporating this agent in first line [18–20] have completed accrual and preliminary results show increased RRs [18, 20] and Progression Free Survival [18].
A subgroup analysis from the Bowel Oncology with Cetuximab Antibody (BOND) trial [21] showed an inverse correlation between RR and the number of prior treatment regimens (18% RR in patients who received only one previous line of CT). Therefore, we designed a phase II trial to explore the potential activity of cetuximab as single agent in previously untreated mCRC patients. Eligible patients were by no means candidate to salvage surgery and, at the same time, had little or no disease-related symptoms, thus making it ethically acceptable to postpone the onset of CT.
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patients and methods |
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patients
Patients were recruited in two centers: the Medical Oncology Unit of Ospedale S. Martino in Genoa and the Oncologia Falck Unit of Ospedale Niguarda Ca’ Granda in Milan. Eligible patients had the following characteristics: (i) histologically confirmed adenocarcinoma of the colon or rectum with metastases in more than one organ, otherwise disease not amenable to salvage surgery; (ii) bidimensionally measurable disease as defined by World Health Organization (WHO) criteria; (iii) Eastern Cooperative Oncology Group (ECOG) performance status (PS) of zero to one; (iv) adequate bone marrow (neutrophils 1500/µl, leukocytes 3000/µl, platelets 100 000/µl), renal (creatinine level 1.5 mg/dl), and hepatic (total bilirubin level 1.5x the upper limit of normal and transaminases 5x the upper limit of normal) functions; and (v) no prior CT for metastatic disease. Prior adjuvant CT and/or radiation therapy was permitted, provided that they were completed at least 6 months before enrollment.
EGFR expression in primary or metastatic tumor was demonstrated by immunohistochemistry in a single reference laboratory by using a commercially available kit (Dako Corporation, Carpentino, CA) according to the manufacturer's instructions. Demonstration of EGFR expression by the tumor was mandatory for enrollment.
This protocol was reviewed and approved by the institutional review board of both participating centers, and all patients gave written informed consent before study entry.
treatment and dose adjustments
Patients received cetuximab i.v. infusion at a loading dose of 400 mg/m2 (over a target of 120 min) on day 1. This loading dose was preceded by a 20-mg test dose to observe for evidence of allergic reactions. All patients were premedicated with chlorfenamine 10 mg i.v. 30 min before cetuximab infusion. Cetuximab infusion was then continued weekly at a maintenance dose of 250 mg/m2 infused in 60 min unless toxicity required dose interruption or reduction. Cetuximab administration was continued until progression of disease or unacceptable toxicity. Upon cetuximab discontinuation, combination CT was started when clinically indicated.
Dose reduction was on the basis of toxic effects evaluated on the day of recycle. Adverse effects were graded according to National Cancer Institute–Common Toxicity Criteria version 3.0. If a patient experienced a grade 3 skin toxicity, cetuximab therapy was delayed for up to two consecutive infusions with no change in the 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 a grade 3 skin toxicity, cetuximab therapy was delayed for up to two consecutive weeks with concomitant dose reductions to 200 and 150 mg/m2, respectively. Patients who experienced a grade 3 allergic or grade 4 anaphylactic reaction were discontinued from the study.
study evaluations
Pretreatment evaluation included immunohistochemical determination of EGFR expression in specimen from either primary or metastatic tumor, a complete medical history and physical exam, complete blood count, chemistry panel, measurements of plasma levels of tumor markers carcinoembryonic antigen (CEA) and CA 19.9, tumor assessment by computed tomography scan within 4 weeks before the enrollment (baseline), and documentation of measurable disease according to WHO criteria. History, physical exam, and laboratory tests were carried out weekly. Computed tomography scans and measurements of plasma levels of tumor markers CEA and CA 19.9 were obtained every 8 weeks. Patients were evaluated for response according to WHO criteria after 8 weeks of treatment. Confirmatory scans were obtained at least 4 weeks after initial documentation of objective complete response (CR) or partial response (PR).
study design and statistical analysis
This is a phase II, single-agent, nonrandomized two-stage trial. The study was conducted according to Simon's two-stage optimal trial design, given an unacceptable response probability 5% (P0) versus the alternative hypothesis of at least 20% response (P1). Alpha and beta errors were set at 5% and 20%, respectively.
The planned sample size was 29 patients, with 10 patients in the first stage. If one or more responses were seen in the first stage, the trial was continued. Ultimately, 44 patients were screened and 39 were treated and evaluated. The higher number was due to more rapid accrual than originally anticipated.
The primary end point of this study was the objective RR (CR + PR).
The secondary end points were time to progression (TTP) and correlation between grade of skin toxicity and RR. In addition, survival was estimated according to Kaplan–Meier method and log-rank test was used to compare survival distributions for the different levels of skin toxicity.
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patient characteristics
From June 2004 to September 2005, tumor samples from 44 patients were screened for EGFR expression by immunohistochemistry (Figure 1). Of these, 42 (97%) were EGFR positive (at least one +). Three patients did not initiate treatment: two withdrew their consent to treatment and one had early PS deterioration. Thirty-nine patients (30 males and nine females) initiated treatment. Six patients discontinued the treatment before the first response evaluation [two allergic reactions, one early death due to progressive disease (PD), and three early PD]. These six patients were counted as failures and all 39 treated patients were included in the intention-to-treat analysis. Their demographics are outlined in Table 1. Median age of the patients was 69 years, with a range of 53–84 years. The median ECOG performance score was 0, with a range of 0–1. The majority of patients had colon cancer as primary tumor site (77%) and only 36% had one metastatic site. At the time of analysis, 67% of the patients had died.
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tumor response and additional efficacy measures
Objective tumor response is summarized in Table 2. The overall RR was 10.2%, with one CR and three PRs. Of note, TTP for the responders were remarkably long: 12 months for the CR, and 6, 9, and 9 months for the PRs. The CR occurred on multiple nonmassive lung and mediastinal nodes metastases from a primary sigmoid cancer. This patient experienced very severe skin toxicity, requiring dose reduction and then discontinuation after
5 months; upon relapse in the lung, rechallenge with cetuximab alone produced only a minor response.
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Thirteen patients (33.3%) had stable disease, five of whom had minor responses. Therefore, the disease control rate was 43.6%. Twenty-two patients (56.4%) had PD within the first tumor evaluation. Median TTP was 2 months and MST was 12.3 months, with a 1-year survival of 51%. This short MST contrasts with that usually obtained in patients treated with CT up front in clinical trials. Sixty-four percent of the patients actually received at least one line of CT after failing this ‘window of opportunity’ trial. The selection of patients (the eligibility criteria called for massive and/or multiple sites of disease) may account for this relatively short MST.
duration of treatment and dose intensity of cetuximab
The median duration of cetuximab treatment was 8 weeks, with a range of 3–48 weeks. Most of the doses were given at the planned full dose of 400 mg/m2 for the loading dose and 250 mg/m2 for the maintenance weekly doses. Twenty-nine patients (74%) received all planned full doses of cetuximab during the study. Four patients (10%) missed either one or two administrations and required dose reductions (three reductions of 20% and one of 40%) due to skin toxicity. Six patients (15%) did not receive all the planned 8 weeks of treatment as a consequence of early discontinuation (early death, n = 1; early PD, n = 3; anaphylactic reactions, n = 2).
toxicity
We observed two severe (grade 4) allergic reactions on the first cetuximab administration. They were related to an anaphylactic mechanism and recovered upon discontinuation of cetuximab infusion and administration of i.v. corticosteroids and anti-hystamines. With the exception of these two allergic reactions, cetuximab monotherapy was generally well tolerated (Table 3). Similar to previous trials with cetuximab, the most common adverse event was skin toxicity, mostly accounted for by skin rash (acneiform eruption) that was present in 33 patients (85%). Only four patients (10%) experienced grade 3 skin rash. In most of the cases, skin symptoms benefited from topic antiacne agents with anti-inflammatory properties; in the case of more severe reactions, oral tetracyclines and oral anti-hystamines were given.
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Other skin-related symptoms were observed as well, in particular, mild xerosis (23%), nail changes (paronychia, 18%; pyogenic granuloma, 5%), and hair changes (trichomegaly, 15%; hypertrichosis, 5%).
Non-skin-related symptoms were generally mild and rather uncommon. Among those, grade 1 or 2 asthenia was more frequently observed (25%), followed by fever (18%), nausea and vomiting (10%), and diarrhea and conjunctivitis (both 8%).
correlation of skin rash with RR and survival
It appears from previous studies that the grade of cetuximab-induced skin toxicity may be predictive of both response and survival [14–16]. In line with this finding, we observed that 10 of 16 patients experiencing grades 2–3 skin rash (62%) achieved either an objective tumor response or a stable disease. On the other hand, only 7 of 23 patients who developed grades 0–1 skin rash (30%) achieved disease stabilization (P < 0.05). Furthermore, we observed a trend towards improved survival with increasing severity of rash. As shown in Table 4, patients with grades 2 and 3 skin toxicity had the longest MST.
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discussion |
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TopAbstractintroductionpatients and methodsresultsdiscussionfundingAcknowledgementsReferences |
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We found that first-line cetuximab monotherapy produced 10% RR, 2 months median TTP, and 12.3 months MST in unselected chemo-naive patients with mCRC noncandidate to potentially radical surgery. These results denote lower activity of cetuximab compared with those of standard CT:
40% RR, 8 months TTP, and 20 months MST on average. We discussed a lot about the ethics of delaying active CT to test the hypothesis that a biological treatment alone impact on the clinical course of advanced colorectal cancer. Our decision to carry out this study was based upon the following considerations and data. First, the selection of patients for whom potentially curative surgery was absolutely contraindicated even in the case of substantial tumor shrinkage; secondly, the clinical trials indicating that delaying immediate aggressive CT may not adversely affect the overall therapeutic outcome in a large proportion of patients [8]; thirdly, the possibility to start standard CT right away in patients failing cetuximab; and finally, the rationale that cetuximab single agent might yield higher RRs and clinical benefit when used in first line than in third/fourth line.
Our data provide empirical evidence that this strategy is not recommendable and should not be pursued further in unselected patients. If we concentrate, however, on the few responding patients, the benefit of the antibody was substantial, lasting several months. This indicates that there is a small, but definite, proportion of patients deriving major and sustained clinical benefit from cetuximab single-agent treatment. This partially contradicts our speculative assumptions. In fact, while the subgroup analysis of the BOND study indicated that cetuximab activity was higher in less intensively treated patients, the 10% RR in the first line found here perfectly matches the 11% RR reported for the third- and fourth-line use of this antibody in several studies [14–17].
Interestingly, our data are very similar to an analogous Spanish ‘window of opportunity trial’ of first-line cetuximab alone in 41 elderly patients, recently reported at a major European meeting (15% RR and 3 months median TTP) [22].
Taken as a whole, the available data on cetuximab so far indicate that this agent in monotherapy produces 10% RR no matter whether used up front or in the late phase of the disease, and an additional 10% when used in combination with irinotecan. The striking similarity of our data with all others’ makes it highly predictable that, even under the best conditions (cetuximab plus combination CT in first line), the incremental benefit of cetuximab will still be limited (in the range of an additional 10% RR). If this is true, the identification of patients with tumors sensitive to cetuximab would increase very substantially the RR to this antibody alone, potentially making it possible to postpone CT at least when palliation is the goal of treatment.
The issue thus becomes how to identify these patients, regardless of the line of treatment where the antibody is used. Despite strong efforts to identify molecular determinants of efficacy, so far no clinically useful biomarkers have been identified in a prospective manner in clinical trials. Promising leads of research include gene copy number of EGFR [23–25], levels and activity of its downstream effectors [26, 27], levels of expression of vascular endothelial growth factor receptor [28], polymorphisms of immunoglobulin G Fc gamma receptor [29], and Kirsten rat sarcoma oncogene or sarcoma viral oncogene (v-raf) homolog B1 mutations [24, 30, 31].
In conclusion, the present study does not support the use of cetuximab as single agent in front-line therapy for mCRC in the general patient population. The attractive hypothesis raised by our findings is that cetuximab does not act as a nonselective incremental agent, but it is very likely to be a selective and powerful therapy for a subset of patients whose characteristics are still to be defined. This observation strongly advocates to identify the determinants of cetuximab activity.
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funding |
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Associazione Italiana per la Ricerca sul Cancro; Oncologia Ca’ Granda Onlus Fondazione.
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We are indebted with the Faculty of the American Society of Clinical Oncology–Federation of European Cancer Societies–American Association for Cancer Research 2004 Flims course, where the protocol was developed. In particular, we are grateful to J. Abruzzese, O. S. Nielsen, and J. Lee for helpful comments on trial design. The study drug was supplied by Merck KGAa. The study was partially supported by Giuseppe Guenzi donation to Oncologia Ca' Granda Onlus (OCGO) Fondazione.
Received for publication August 30, 2007. Revision received October 5, 2007. Accepted for publication October 8, 2007.
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