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The Oncologist, Vol. 13, No. 2, 113-119, February 2008; doi:10.1634/theoncologist.2007-0201
© 2008 AlphaMed Press

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Gastrointestinal Cancer

Administration of Cetuximab Every 2 Weeks in the Treatment of Metastatic Colorectal Cancer: An Effective, More Convenient Alternative to Weekly Administration?

Josep Taberneroa, Per Pfeifferb, Andrés Cervantesc

aVall d'Hebron University Hospital, Barcelona, Spain; bOdense University Hospital, Odense C, Denmark; cHospital Clínico, Universidad de Valencia, Valencia, Spain

Key Words. Cetuximab • Colorectal cancer • Every two weeks • Pharmacodynamics • Pharmacokinetics • Weekly

Correspondence: Josep Tabernero, M.D., Medical Oncology Department, Vall d'Hebron University Hospital, P. Vall d'Hebron, 119–129, 08035, Barcelona, Spain. Telephone: 34-93-274-6085; Fax: 34-93-274-6059; e-mail: jtabernero{at}vhebron.net

Received October 22, 2007; accepted for publication December 3, 2007.

Disclosure: J.T. has acted as a consultant to Merck KGaA. No other potential conflicts of interest were reported by the authors, planners, reviewers, or staff managers of this article.


   ABSTRACT
Top
 Footnotes
 Abstract
Introduction
 Pharmacokinetics of Cetuximab
 Pharmacodynamics
 Efficacy
 Safety
 Discussion
 References
 
The primary purpose of this paper is to present the available evidence for the administration of cetuximab on an every-2-weeks basis in combination with irinotecan in metastatic colorectal cancer (mCRC). Cetuximab is an epidermal growth factor receptor–targeted IgG1 monoclonal antibody that is approved for use in combination with irinotecan or as monotherapy in the treatment of mCRC. The currently approved dosing regimen for cetuximab is a 400-mg/m2 initial dose followed by 250 mg/m2 weekly. Many commonly used chemotherapy agents for mCRC (including irinotecan alone or in combination with 5-fluorouracil [5-FU]/folinic acid [FA] and oxaliplatin plus 5-FU/FA) are administered on an every-2-weeks basis. The ability to synchronize the administration of cetuximab and concomitant chemotherapy is desirable for both patients and health care workers. A cetuximab dose of 500 mg/m2 every 2 weeks exhibited predictable pharmacokinetics, which were similar to those of the approved weekly dosing regimen. Active serum concentrations of cetuximab were maintained throughout the 2-week dosing period with this regimen. There was no difference between the dosing regimens on pharmacodynamic parameters in skin. The efficacy and safety of the every-2-weeks dosing regimen were similar to those reported for the approved weekly dosing regimen. The indication from these preliminary findings is that every-2-weeks administration of cetuximab (500 mg/m2) may be a potentially convenient alternative to the approved weekly dosing regimen of 250 mg/m2 (following an initial dose of 400 mg/m2) in the treatment of mCRC.


   INTRODUCTION
Top
 Footnotes
 Abstract
 Introduction
Pharmacokinetics of Cetuximab
 Pharmacodynamics
 Efficacy
 Safety
 Discussion
 References
 
The epidermal growth factor receptor (EGFR) has been widely investigated as a key target for cancer therapy [1–3]. It is expressed in many human tumor types, including colorectal cancer (CRC) [4–7], where expression is often associated with poor clinical prognosis [8, 9]. Cetuximab is an IgG1 monoclonal antibody that specifically targets the EGFR with high affinity and competitively inhibits ligand binding, thereby disrupting EGFR signaling [1, 10, 11]. Cetuximab thereby prevents EGFR dimerization and subsequent tyrosine kinase activation [12]. It also stimulates EGFR internalization and degradation [13–15]. Cetuximab-induced inhibition of EGFR signaling leads to downregulation of downstream targets, such as phosphorylated mitogen-activated protein kinase (pMAPK) and pAkt. It is also associated with reduced Ki67 (cell proliferation antigen) expression and increased p27 (cyclin-dependent kinase inhibitor) expression [1, 16]. Cetuximab inhibition of EGFR leads to inhibition of tumor growth, invasion, and metastasis, DNA damage repair, and angiogenesis [1, 2, 17, 18]. In addition, it demonstrates strong synergy with chemotherapy in human CRC tumor models [19, 20].

Cetuximab is approved in a number of different countries for use in patients with EGFR-expressing metastatic CRC (mCRC) who have failed on previous irinotecan-containing therapy, either in combination with irinotecan or as monotherapy. Clinical studies are currently investigating the use of cetuximab in the first-line setting in combination with irinotecan- or oxaliplatin-based regimens. It is also approved for the treatment of locally advanced squamous cell carcinoma of the head and neck (SCCHN), in combination with radiotherapy, and in some countries as monotherapy for recurrent and/or metastatic SCCHN after failure on platinum-based therapy. In general, cetuximab is well tolerated and does not exacerbate the side effects of irinotecan or oxaliplatin. The main side effects are skin reactions, particularly an acne-like rash that is characteristic of treatment with many EGFR inhibitors. Such skin reactions are generally manageable. Other less frequently observed side effects associated with cetuximab treatment are diarrhea, fatigue, and hypomagnesemia.

The approved dosing regimen of cetuximab, both as monotherapy and in combination with chemotherapy, is an initial i.v. infusion of 400 mg/m2 on day 1 with subsequent weekly doses of 250 mg/m2 [21]. While this regimen is undoubtedly active, the weekly administration of cetuximab is out of step with administration of the chemotherapy regimens with which cetuximab is commonly combined. In mCRC progressing on chemotherapy, irinotecan is often administered at a dose of 180 mg/m2 every 2 weeks [4]. Similarly, in the first-line setting, combinations of infusional 5-fluorouracil (5-FU)/folinic acid plus irinotecan (FOLFIRI) [22] or oxaliplatin [23] are frequently administered on an every-2-weeks basis. The option to synchronize the administration of cetuximab and concomitant chemotherapy would reduce the impact of treatment administration on patients' lives and simplify treatment administration for health care workers. It is also reasonable to assume that a simplified schedule may reduce the costs associated with cetuximab administration.

In assessing the activity of a modified dosing regimen, a number of different parameters need to be considered. Thus, the pharmacokinetic and pharmacodynamic aspects (i.e., effects on the EGFR signaling pathway) of cetuximab should be considered alongside the safety and efficacy of both the approved and modified dosing regimens in different treatment settings. In this paper, we present data for these different parameters from studies using the approved, weekly cetuximab dosing regimen and compare these with recently reported findings using an every-2-weeks administration regimen of cetuximab.


   PHARMACOKINETICS OF CETUXIMAB
Top
 Footnotes
 Abstract
 Introduction
 Pharmacokinetics of Cetuximab
Pharmacodynamics
 Efficacy
 Safety
 Discussion
 References
 
Pharmacokinetics of the Approved Dosing Schedule
The pharmacokinetic profile of cetuximab was derived from 19 clinical studies in patients with a range of solid tumors, including CRC [24]. As is typical of pharmacokinetic studies in oncology, patients had frequently undergone several prior lines of therapy. Cetuximab was administered either as monotherapy or in combination with chemotherapy or radiotherapy. Results from individual studies were analyzed by noncompartmental pharmacokinetic analysis. A pooled analysis of data across the studies demonstrated that, at single doses of cetuximab in the range of 5–500 mg/m2, largely linear relationships with dose were observed for the maximum serum concentration (Cmax) and the area under the concentration–time curve extrapolated to infinity (AUC0-{infty}) [24]. Exposure to cetuximab was predictable at doses of 200 mg/m2 and above. While dose-dependent relationships were observed for the terminal elimination half-life (t1/2) and total body clearance (CL), these were seen mainly at lower doses of cetuximab. With the approved dosing regimen, CL values were constant (0.02 l/hour/m2), showing that the pharmacokinetics were predictable within this dose range.

Multiple dose studies have demonstrated that the pharmacokinetic parameters—CL, AUC, t1/2, and volume of distribution at steady state (Vss)—are similar after single and multiple doses of cetuximab at the approved dosing regimen (Table 1) [24]. Pharmacokinetic parameters remained constant for up to four cetuximab doses at the approved dosing regimen.


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  		Table 1. Pharmacokinetic parameters for cetuximab after multiple dosing at the approved dosing regimen [24]

 
A population pharmacokinetic analysis on data from cetuximab clinical studies was conducted to identify if any patient subpopulations exhibited altered pharmacokinetics [25]. Data from 960 patients across 19 clinical studies were included. A covariate analysis included data on: demographics (age, weight, height, body surface area, sex, and ethnicity), hepatic and renal function, cancer type, concurrent therapy, EGFR status, clinical response, and the presence of skin rash. None of the covariates investigated had a clinically relevant impact on cetuximab pharmacokinetics, confirming the predictability of cetuximab pharmacokinetics at the approved dosing regimen across a wide range of patients.

Finally, a study in 13 evaluable patients with advanced solid tumors who were receiving cetuximab (approved dosing regimen) and irinotecan (350 mg/m2 every 3 weeks) found no significant pharmacokinetic interaction between cetuximab and irinotecan [26].

Pharmacokinetics of Modified Dosing Schedules
A number of studies have investigated the use of escalated doses of cetuximab administered on a weekly basis. A phase I study compared the use of cetuximab monotherapy at the approved dosing regimen with that of weekly doses of 250 mg/m2 or 350 mg/m2 (without the initial higher dose of cetuximab) in 49 patients with mCRC failing previous chemotherapy [27]. As expected, the mean CL, t1/2, and Vss were in good agreement across the three treatment groups. There were dose-related 30%–50% higher levels of Cmax and AUC in patients receiving 350 mg/m2 compared with those receiving 250 mg/m2, confirming the linear pharmacokinetics of these dosing schedules. In patients receiving the highest dose (350 mg/m2), there were moderately higher cetuximab serum trough concentrations (Cmin, the lowest observed level of cetuximab) with successive doses. From week 4, trough values with this dose were fairly constant, indicating that steady-state levels had been reached, and remained higher than those observed with the 250-mg/m2 per week dose.

In a randomized phase II study investigating the relationship between cetuximab-associated rash and response to treatment, patients received cetuximab either at the approved dose or at escalating doses (50 mg/m2 every 2 weeks) up to a maximum of 500 mg/m2 per week [28]. The pharmacokinetics were in line with those reported previously, and both the mean AUC and the Cmin increased linearly with dose.

Data on the pharmacokinetics of every-2-weeks dosing of cetuximab are available from the preliminary results of a two-part, phase I study in patients with EGFR-expressing mCRC who had not received previous chemotherapy for metastatic CRC [29]. In the first part of the study, patients received 6 weeks of treatment with either the approved dosing schedule of cetuximab (400-mg/m2 initial dose followed by 250 mg/m2 per week) or doses of 400, 500, 600, and 700 mg/m2 every 2 weeks. It was during this first part of the study that the complete pharmacokinetic profile was obtained. The primary endpoint of the study was to determine the maximum-tolerated dose of cetuximab administered every 2 weeks, based on the safety profile. Secondary endpoints included assessment of the pharmacokinetic parameters and determination of the pharmacodynamic effects of weekly and every-2-weeks administered cetuximab. Efficacy assessments following the combination of cetuximab and FOLFIRI are planned in the second part of the study.

Data from 29 patients were available for the preliminary analysis. The pharmacokinetics at week 5 of treatment for cetuximab at the approved dosing regimen and at doses of 400 mg/m2 and 500 mg/m2 administered on an every-2-weeks basis are shown in Table 2. The pharmacokinetics of the approved dosing regimen were in line with those reported previously for this regimen, and shown in Table 1. Furthermore, the pharmacokinetics of the weekly 250 mg/m2 and the every-2-weeks 500 mg/m2 cetuximab regimens were comparable. At the 500-mg/m2 dose, the AUC after 2 weeks was equivalent to the exposure to cetuximab achieved with 2 weeks of dosing of the approved regimen. Trough, or minimal, concentrations of cetuximab, measured at weeks 3, 5, and 7, for the every-2-weeks 500-mg/m2 dose were close to those reported for the weekly 250-mg/m2 dose. Thus, over a 2-week dosing interval, a patient's minimal exposure to cetuximab is the same with an every-2-weeks dose of 500 mg/m2 and a weekly dose of 250 mg/m2. At a dose of 400 mg/m2, however, the AUC after 2 weeks represented only approximately 80% of the exposure to cetuximab achieved with 2 weeks of the approved dosing regimen and trough cetuximab concentrations were only about half of those achieved with the approved dosing regimen.


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  		Table 2. Phase I study comparing weekly and every-2-weeks dosing regimens for cetuximab in metastatic colorectal cancer: Patient characteristic pharmacokinetic parameters after multiple dosing (week 5 of treatment) [29]

 

   PHARMACODYNAMICS
Top
 Footnotes
 Abstract
 Introduction
 Pharmacokinetics of Cetuximab
 Pharmacodynamics
Efficacy
 Safety
 Discussion
 References
 
The effects of different doses of cetuximab on markers of EGFR signaling—pEGFR, pMAPK, Ki67, and p27—have also been investigated [29]. Preliminary data from an analysis of a limited number of skin biopsies, taken at baseline and day 28, showed no major differences in the inhibition of EGFR signaling between cetuximab administered with the weekly and every-2-weeks dosing regimens.


   EFFICACY
Top
 Footnotes
 Abstract
 Introduction
 Pharmacokinetics of Cetuximab
 Pharmacodynamics
 Efficacy
Safety
 Discussion
 References
 
The efficacy of cetuximab in mCRC was first demonstrated by Saltz et al. [30] in two single-arm, phase II studies in patients with EGFR-expressing mCRC that had progressed on irinotecan-containing therapy. In the first study, 121 patients were treated with irinotecan at the same dose and schedule that the disease had progressed on, with the addition of cetuximab at the subsequently approved dosing regimen (400-mg/m2 initial dose followed by 250 mg/m2 per week thereafter) [30]. Seventeen percent of patients achieved a partial response and 31% had stable disease or a minor response. The encouraging results of that trial led to the evaluation of the antitumor activity of single-agent cetuximab in a similar population of patients. Fifty-seven patients were treated with cetuximab at the same dose and schedule as in the previous study, with 9% of patients achieving a partial response and another 37% achieving either stable disease or a minor response [7]. After these studies, a phase II randomized trial (the Bowel Oncology with Cetuximab Antibody [BOND] study) comparing cetuximab alone with cetuximab plus irinotecan in patients with EGFR-expressing mCRC that had progressed on irinotecan-containing therapy was conducted (Table 3) [4]. Patients received cetuximab at the subsequently approved dosing regimen (400-mg/m2 initial dose followed by 250 mg/m2 per week thereafter) plus irinotecan at the same dose and schedule that the patient had progressed on. The most commonly used irinotecan regimen was 180 mg/m2 every 2 weeks (57% of patients), followed by 350 mg/m2 every 3 weeks (25%). In that study, 63% of patients had previously received oxaliplatin. Cetuximab plus irinotecan was associated with a response rate of 23%, a median time to progression (TTP) of 4.1 months, and a median overall survival (OS) time of 8.6 months. These findings were subsequently confirmed by a study conducted in similar patients in the community setting (the Monoclonal Antibody Erbitux in a European Pre-License [MABEL] study) [31]. In this large, multicenter investigation (n = 1,147), the proportions of patients receiving the various irinotecan regimens were similar to those in the BOND study: 58% received 180 mg/m2 every 2 weeks and 31% received 350 mg/m2 every 3 weeks [31]. In this study, all patients had progressed on irinotecan-containing therapy and 69% of patients had also received oxaliplatin.


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  		Table 3. Efficacy of cetuximab plus irinotecan in patients with metastatic colorectal cancer failing on previous chemotherapy: Comparison of weekly and every-2-weeks cetuximab dosing

 
While the pharmacokinetic and pharmacodynamic data indirectly suggest the clinical equivalence of the every-2-weeks and weekly cetuximab dosing regimens, direct demonstration of the efficacy equivalence of the different regimens is required. Early indications are that such equivalence is indeed the case. In a recent nonrandomized study, patients with mCRC failing previous 5-FU, irinotecan, and oxaliplatin received irinotecan at a dose of 180 mg/m2 every 2 weeks in combination with cetuximab at the standard dosing regimen (400-mg/m2 initial dose and 250 mg/m2 subsequently) (n = 65) or according to a simplified dosing regimen of 500 mg/m2 every 2 weeks (n = 40) [32]. The efficacy of the every-2-weeks cetuximab dosing regimen was shown to be similar to that of the weekly dosing regimen (Table 3). Response rates were 22% for the every-2-weeks regimen and 20% with the weekly regimen. The corresponding median TTP and OS time were 4.8 and 5.4 months and 9.8 and 10.4 months, respectively. The efficacy achieved with the every-2-weeks cetuximab dosing regimen was remarkably similar to the efficacy of the weekly regimen used in the BOND and MABEL studies (Table 3). While this is a small study, the findings are a good indication that dosing of cetuximab at 500 mg/m2 every 2 weeks is as effective as weekly dosing of cetuximab at 250 mg/m2.


   SAFETY
Top
 Footnotes
 Abstract
 Introduction
 Pharmacokinetics of Cetuximab
 Pharmacodynamics
 Efficacy
 Safety
Discussion
 References
 
At the approved dosing regimen, cetuximab is generally well tolerated. The most commonly reported side effect is an acne-like skin rash, which is seen in >80% of patients. In most patients, the rash is grade 1 or 2 and is easily manageable. Cetuximab does not increase the side effects of chemotherapy, including irinotecan and oxaliplatin [4, 33–35].

The every-2-weeks administration of a high dose of cetuximab is not associated with a greater incidence of grade 3 or 4 adverse events than weekly administration of the lower, approved dose [29, 32]. Table 4 shows the grade 3 or 4 adverse events reported in studies investigating the use of cetuximab plus irinotecan in patients with mCRC progressing on previous chemotherapy. The adverse events reported are typical of those expected with cetuximab plus irinotecan. The adverse event categories shown in Table 4 are restricted to those that were reported in the study of every-2-weeks cetuximab.


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  		Table 4. Grade 3 or 4 adverse events reported with cetuximab plus irinotecan in patients with metastatic colorectal cancer failing on previous chemotherapy: Comparison of weekly and every-2-weeks cetuximab dosing

 

   DISCUSSION
Top
 Footnotes
 Abstract
 Introduction
 Pharmacokinetics of Cetuximab
 Pharmacodynamics
 Efficacy
 Safety
 Discussion
References
 
This review provides preliminary pharmacokinetic, pharmacodynamic, efficacy, and safety evidence that every-2-weeks administration of cetuximab at a dose of 500 mg/m2 may be a potentially convenient alternative to the approved weekly dosing regimen of 250 mg/m2 (following an initial dose of 400 mg/m2) in the treatment of mCRC.

A dose of 500 mg/m2 every 2 weeks was shown to have predictable pharmacokinetics, which are similar to those of the approved weekly dosing regimen. In the steady state, the mean AUC of the 500-mg/m2 dose over a 2-week period was twice that of the 250-mg/m2 dose over a 1-week period, indicating that exposure to cetuximab is similar with the two dosing regimens [29]. Importantly, active serum concentrations of cetuximab with the every-2-weeks dose were maintained throughout the dosing period, and minimum serum levels were close to those observed for the approved dosing regimen. Pharmacodynamic assessments on skin tissue demonstrated that disruption of EGFR signaling appeared to be independent of the dosing regimen of cetuximab. There were no differences between the weekly and every-2-weeks dosing regimens in the inhibition of pEGFR, pMAPK, and Ki67, and the stimulation of p27 [29]. In terms of efficacy, an every-2-weeks dose of 500 mg/m2 of cetuximab in combination with irinotecan gave a strikingly similar response rate (23%) and median TTP (4.8 months) [32] to those of the approved dosing regimen plus irinotecan (23% and 4.1 months, respectively) [4] in patients who had progressed on previous chemotherapy. Finally, a higher dose of cetuximab administered on an every-2-weeks basis is not associated with a greater incidence of adverse events than the approved weekly dose.

The results presented here for the every-2-weeks dosing regimen are from small studies and the data from the ongoing phase I study are preliminary. Nevertheless, the data provide early evidence that every-2-weeks administration of cetuximab at a dose of 500 mg/m2 is as effective and well tolerated as a weekly dose of 250 mg/m2. The efficacy data presented here are for the use of the every-2-weeks regimen in the treatment of patients who have progressed on previous treatment. Based on the pharmacokinetic similarities of the two dosing regimens in the first-line setting [29], it is reasonable to anticipate that the efficacy and safety of the every-2-weeks dosing regimen will also be similar to that observed with the approved dosing regimen. Although it would be desirable to confirm the efficacy equivalence of the two dosing schedules in a noninferiority, randomized trial of the weekly versus every-2-weeks regimens of cetuximab, it is not expected that such a trial could now be conducted in this setting. Nevertheless, a number of phase II studies are currently investigating the use of cetuximab administered every 2 weeks in combination with irinotecan- or oxaliplatin-based chemotherapy in both the first-line and subsequent-line treatment of mCRC.


   FOOTNOTES
 
Conception/design: Josep Tabernero

Collection/assembly of data: Josep Tabernero

Data analysis: Josep Tabernero

Manuscript writing: Josep Tabernero, Per Pfeiffer, Andrés Cervantes

Final approval of manuscript: Josep Tabernero, Per Pfeiffer, Andrés Cervantes


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Top
 Footnotes
 Abstract
 Introduction
 Pharmacokinetics of Cetuximab
 Pharmacodynamics
 Efficacy
 Safety
 Discussion
 References
 

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THE ONCOLOGIST STEM CELLS CME ALPHAMED PRESS JOURNALS