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Mechanism of Action

The epidermal growth factor receptor (EGFR, HER1, c-ErbB-1) is a transmembrane glycoprotein that is a member of a subfamily of type I receptor tyrosine kinases including EGFR, HER2, HER3, and HER4. The EGFR is constitutively expressed in many normal epithelial tissues, including the skin and hair follicle. Expression of EGFR is also detected in many human cancers including those of the head and neck, colon, and rectum.

Cetuximab binds specifically to the EGFR on both normal and tumor cells, and competitively inhibits the binding of epidermal growth factor (EGF) and other ligands, such as transforming growth factor-alpha. In vitro assays and in vivo animal studies have shown that binding of cetuximab to the EGFR blocks phosphorylation and activation of receptor-associated kinases, resulting in inhibition of cell growth, induction of apoptosis, and decreased matrix metalloproteinase and vascular endothelial growth factor production. Signal transduction through the EGFR results in activation of wild-type KRAS protein. However, in cells with activating KRAS somatic mutations, the mutant KRAS protein is continuously active and appears independent of EGFR regulation.

In vitro, cetuximab can mediate antibody-dependent cellular cytotoxicity (ADCC) against certain human tumor types. In vitro assays and in vivo animal studies have shown that cetuximab inhibits the growth and survival of tumor cells that express the EGFR. No antitumor effects of cetuximab were observed in human tumor xenografts lacking EGFR expression. The addition of cetuximab to radiation therapy or irinotecan in human tumor xenograft models in mice resulted in an increase in anti-tumor effects compared to radiation therapy or chemotherapy alone.

Pharmacokinetics

Erbitux administered as monotherapy or in combination with concomitant chemotherapy or radiation therapy exhibits nonlinear pharmacokinetics. The area under the concentration time curve (AUC) increased in a greater than dose proportional manner while clearance of cetuximab decreased from 0.08 to 0.02 L/h/m² as the dose increased from 20 to 200 mg/m², and at doses > 200 mg/m², it appeared to plateau. The volume of the distribution for cetuximab appeared to be independent of dose and approximated the vascular space of 2–3 L/m².

Following the recommended dose regimen (400 mg/m² initial dose; 250 mg/m² weekly dose), concentrations of cetuximab reached steady-state levels by the third weekly infusion with mean peak and trough concentrations across studies ranging from 168 to 235 and 41 to 85 μg/mL, respectively. The mean half-life of cetuximab was approximately 112 hours (range 63–230 hours). The pharmacokinetics of cetuximab were similar in patients with SCCHN and those with colorectal cancer.

Based on a population pharmacokinetic analysis, female patients with colorectal cancer had a 25% lower intrinsic clearance of cetuximab than male patients. Qualitatively similar, but smaller gender differences in cetuximab clearance were observed in patients with SCCHN. The gender differences in clearance do not necessitate any alteration of dosing because of a similar safety profile.

Animal Pharmacology and/or Toxicology

In cynomolgus monkeys, cetuximab, when administered at doses of approximately 0.4 to 4 times the weekly human exposure (based on total body surface area), resulted in dermatologic findings, including inflammation at the injection site and desquamation of the external integument. At the highest dose level, the epithelial mucosa of the nasal passage, esophagus, and tongue were similarly affected, and degenerative changes in the renal tubular epithelium occurred. Deaths due to sepsis were observed in 50% (5/10) of the animals at the highest dose level beginning after approximately 13 weeks of treatment.

Clinical Studies

Squamous Cell Carcinoma of the head and Neck (SCChN)

Study 1 was a randomized, multicenter, controlled trial of 424 patients with locally or regionally advanced SCCHN. Patients with Stage III/IV SCCHN of the oropharynx, hypopharynx, or larynx with no prior therapy were randomized (1:1) to receive either Erbitux plus radiation therapy or radiation therapy alone. Stratification factors were Karnofsky Performance Status (60–80 versus 90–100), nodal stage (N0 versus N+), tumor stage (T₁–3 versus T4 using American Joint Committee on Cancer 1998 staging criteria), and radiation therapy fractionation (concomitant boost versus once-daily versus twice-daily). Radiation therapy was administered for 6–7 weeks as once daily, twice daily, or concomitant boost. Erbitux was administered as a 400 mg/m² initial dose beginning one week prior to initiation of radiation therapy, followed by 250 mg/m² weekly administered 1 hour prior to radiation therapy for the duration of radiation therapy (6–7 weeks).

Of the 424 randomized patients, the median age was 57 years, 80% were male, 83% were Caucasian, and 90% had baseline Karnofsky Performance Status ≥ 80. There were 258 patients enrolled in US sites (61%). Sixty percent of patients had oropharyngeal, 25% laryngeal, and 15% hypopharyngeal primary tumors; 28% had AJCC T4 tumor stage. Fifty-six percent of the patients received radiation therapy with concomitant boost, 26% received once-daily regimen, and 18% twice-daily regimen.

The main outcome measure of this trial was duration of locoregional control. Overall survival was also assessed. Results are presented in Table 4.

Table 4: Study 1: Clinical Efficacy in Locoregionally Advanced SCCHN

Study 2 was a single-arm, multicenter clinical trial in 103 patients with recurrent or metastatic SCCHN. All patients had documented disease progression within 30 days of a platinum-based chemotherapy regimen. Patients received a 20-mg test dose of Erbitux on Day 1, followed by a 400-mg/m² initial dose, and 250 mg/m² weekly until disease progression or unacceptable toxicity.

The median age was 57 years, 82% were male, 100% Caucasian, and 62% had a Karnofsky Performance Status of ≥ 80.

The objective response rate was 13% (95% confidence interval 7%–21%). Median duration of response was 5.8 months (range 1.2–5.8 months).

Colorectal Cancer

Erbitux Clinical Trials in EGFR-Expressing, Recurrent, Metastatic Colorectal Cancer

Study 3 was a multicenter, open-label, randomized, clinical trial conducted in 572 patients with EGFR-expressing, previously treated, recurrent, metastatic colorectal cancer (mCRC). Patients were randomized (1:1) to receive either Erbitux plus best supportive care (BSC) or BSC alone. Erbitux was administered as a 400-mg/m² initial dose, followed by 250 mg/m² weekly until disease progression or unacceptable toxicity.

Of the 572 randomized patients, the median age was 63 years, 64% were male, 89% were Caucasian, and 77% had baseline ECOG Performance Status of 0–1. All patients were to have received and progressed on prior therapy including an irinotecancontaining regimen and an oxaliplatin-containing regimen.

The main outcome measure of the study was overall survival. The results are presented in Figure 1.

Figure 1: Kaplan Meier Curve for Overall Survival in Patients with Metastatic Colorectal Cancer

Study 4 was a multicenter, clinical trial conducted in 329 patients with EGFRexpressing recurrent mCRC. Patients were randomized (2:1) to receive either Erbitux plus irinotecan (218 patients) or Erbitux monotherapy (111 patients). Erbitux was administered as a 400-mg/m² initial dose, followed by 250 mg/m² weekly until disease progression or unacceptable toxicity. In the Erbitux plus irinotecan arm, irinotecan was added to Erbitux using the same dose and schedule for irinotecan as the patient had previously failed. Acceptable irinotecan schedules were 350 mg/m² every 3 weeks, 180 mg/m² every 2 weeks, or 125 mg/m² weekly times four doses every 6 weeks. Of the 329 patients, the median age was 59 years, 63% were male, 98% were Caucasian, and 88% had baseline Karnofsky Performance Status ≥ 80. Approximately two-thirds had previously failed oxaliplatin treatment.

The efficacy of Erbitux plus irinotecan or Erbitux monotherapy, based on durable objective responses, was evaluated in all randomized patients and in two prespecified subpopulations: irinotecan refractory patients, and irinotecan and oxaliplatin failures. In patients receiving Erbitux plus irinotecan, the objective response rate was 23% (95% confidence interval 18%–29%), median duration of response was 5.7 months, and median time to progression was 4.1 months. In patients receiving Erbitux monotherapy, the objective response rate was 11% (95% confidence interval 6%–18%), median duration of response was 4.2 months, and median time to progression was 1.5 months. Similar response rates were observed in the predefined subsets in both the combination arm and monotherapy arm of the study.

Lack of Efficacy of Anti-EGFR Monoclonal Antibodies in Patients With mCRC Containing KRAS Mutations

Retrospective analyses as presented in Table 5 across seven randomized clinical trials suggest that anti-EGFR monoclonal antibodies are not effective for the treatment of patients with mCRC containing KRAS mutations. In these trials, patients received standard of care (ie, BSC or chemotherapy) and were randomized to receive either an anti-EGFR antibody (cetuximab or panitumumab) or no additional therapy. In all studies, investigational tests were used to detect KRAS mutations in codon 12 or 13. The percentage of study populations for which KRAS status was assessed ranged from 23% to 92%.

Table 5: Retrospective Analyses of Treatment Effect in the Subset of Patients with mCRC Containing KRAS Mutations Enrolled in Randomized Clinical Trials

Last reviewed on RxList: 11/9/2011
This monograph has been modified to include the generic and brand name in many instances.