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Erbitux (Cetuximab) - Description and Clinical Pharmacology

 
 



DESCRIPTION

ERBITUX™ (Cetuximab) is a recombinant, human/mouse chimeric monoclonal antibody that binds specifically to the extracellular domain of the human epidermal growth factor receptor (EGFR). ERBITUX is composed of the Fv regions of a murine anti-EGFR antibody with human IgG1 heavy and kappa light chain constant regions and has an approximate molecular weight of 152 kDa. ERBITUX is produced in mammalian (murine myeloma) cell culture.

ERBITUX is a sterile, clear, colorless liquid of pH 7.0 to 7.4, which may contain a small amount of easily visible, white, amorphous, Cetuximab particulates. Each single-use, 50-mL vial contains 100 mg of Cetuximab at a concentration of 2 mg/mL and is formulated in a preservative-free solution containing 8.48 mg/mL sodium chloride, 1.88 mg/mL sodium phosphate dibasic heptahydrate, 0.42 mg/mL sodium phosphate monobasic monohydrate, and Water for Injection, USP.

CLINICAL PHARMACOLOGY

GENERAL

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

In vitro assays and in vivo animal studies have shown that ERBITUX inhibits the growth and survival of tumor cells that over-express the EGFR. No anti-tumor effects of ERBITUX were observed in human tumor xenografts lacking EGFR expression. The addition of ERBITUX to irinotecan or irinotecan plus 5-fluorouracil in animal studies resulted in an increase in anti-tumor effects compared to chemotherapy alone.

HUMAN PHARMACOKINETICS

ERBITUX administered as monotherapy or in combination with concomitant chemotherapy or radiotherapy exhibits nonlinear pharmacokinetics. The area under the concentration time curve (AUC) increased in a greater than dose proportional manner as the dose increased from 20 to 400 mg/m2. ERBITUX clearance (CL) 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 (Vd) for ERBITUX appeared to be independent of dose and approximated the vascular space of 2-3 L/m2.

Following a 2-hour infusion of 400 mg/m2 of ERBITUX, the maximum mean serum concentration (Cmax) was 184 µg/mL (range: 92-327 µg/mL) and the mean elimination half-life was 97 hours (range 41-213 hours). A 1-hour infusion of 250 mg/m2 produced a mean Cmax of 140 µg/mL (range 120-170 µg/mL). Following the recommended dose regimen (400 mg/m2 initial dose/250 mg/m2 weekly dose), ERBITUX concentrations 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 was 114 hours (range 75-188 hours).

SPECIAL POPULATIONS

A population pharmacokinetic analysis was performed to explore the potential effects of selected covariates including race, gender, age, and hepatic and renal function on ERBITUX pharmacokinetics.

Female patients had a 25% lower intrinsic ERBITUX clearance than male patients. The toxicity profile was similar in males and females. Definitive conclusions regarding the comparability in efficacy cannot be made given the small number of patients with objective tumor response.

ERBITUX has not been studied in pediatric populations.

CLINICAL STUDIES

The efficacy and safety of ERBITUX alone or in combination with irinotecan were studied in a randomized, controlled trial (329 patients) and in combination with irinotecan in an open-label, single-arm trial (138 patients). ERBITUX was further evaluated as a single agent in a third clinical trial (57 patients). Safety data from 111 patients treated with single-agent ERBITUX was also evaluated. All trials studied patients with EGFR-expressing metastatic colorectal cancer, whose disease had progressed after receiving an irinotecan-containing regimen.

RANDOMIZED, CONTROLLED TRIAL

A multicenter, randomized, controlled clinical trial was conducted in 329 patients randomized to receive either ERBITUX plus irinotecan (218 patients) or ERBITUX monotherapy (111 patients). In both arms of the study, ERBITUX was administered as a 400 mg/m2 initial dose, followed by 250 mg/m2 weekly until disease progression or unacceptable toxicity. All patients received a 20-mg test dose on Day 1. 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. An Independent Radiographic Review Committee (IRC), blinded to the treatment arms, assessed both the progression on prior irinotecan and the response to protocol treatment for all patients.

Of the 329 randomized patients, 206 (63%) were male. The median age was 59 years (range 26-84), and the majority was Caucasian (323, 98%). Eighty-eight percent of patients had baseline Karnofsky Performance Status >/=80. Fifty-eight percent of patients had colon cancer and 40% rectal cancer. Approximately two-thirds (63%) of patients had previously failed oxaliplatin treatment.

The efficacy of ERBITUX plus irinotecan or ERBITUX monotherapy was evaluated in all randomized patients.

Analyses were also conducted in two pre-specified subpopulations: irinotecan refractory and irinotecan and oxaliplatin failures. The irinotecan refractory population was defined as randomized patients who had received at least two cycles of irinotecan-based chemotherapy prior to treatment with ERBITUX, and had independent confirmation of disease progression within 30 days of completion of the last cycle of irinotecan-based chemotherapy.

The irinotecan and oxaliplatin failure population was defined as irinotecan refractory patients who had previously been treated with and failed an oxaliplatin-containing regimen.

The objective response rates (ORR) in these populations are presented in Table 1.

Table 1: Objective Response Rates per Independent Review
ERBITUX + Irinotecan ERBITUX Monotherapy Difference (95% CI a)
Populations n ORR (%) n ORR (%) % p-value CMH b
All Patients 218 22.9 111 10.8 12.1 (4.1 - 20.2) 0.007
· Irinotecan-Oxaliplatin Failure 80 23.8 44 11.4 12.4 (-0.8 - 25.6) 0.09
· Irinotecan Refractory 132 25.8 69 14.5 11.3 (0.1 - 22.4) 0.07
a 95% confidence interval for the difference in objective response rates.
b Cochran-Mantel-Haenszel test.

The median duration of response in the overall population was 5.7 months in the combination arm and 4.2 months in the monotherapy arm. Compared with patients randomized to ERBITUX alone, patients randomized to ERBITUX and irinotecan experienced a significantly longer median time to disease progression (see Table 2).

Table 2: Time to Progression per Independent Review
Populations ERBITUX + Irinotecan (median) ERBITUX Monotherapy (median) Hazard Ratio
(95% CI a)
Log-rank p-value
All Patients 4.1 mo 1.5 mo 0.54 (0.42 - 0.71) <0.001
· Irinotecan-Oxaliplatin Failure 2.9 mo 1.5 mo 0.48 (0.31 - 0.72) <0.001
· Irinotecan Refractory 4.0 mo 1.5 mo 0.52 (0.37 - 0.73) <0.001
a Hazard ratio of ERBITUX + irinotecan: ERBITUX monotherapy with 95% confidence interval.

SINGLE-ARM TRIALS

ERBITUX, in combination with irinotecan, was studied in a single-arm, multicenter, open-label clinical trial in 138 patients with EGFR-expressing metastatic colorectal cancer who had progressed following an irinotecan-containing 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. Patients received the same dose and schedule for irinotecan as the patient had previously failed. Acceptable irinotecan schedules were 350 mg/m2 every 3 weeks or 125 mg/m2 weekly times four doses every 6 weeks. Of 138 patients enrolled, 74 patients had documented progression to irinotecan as determined by an IRC. The overall response rate was 15% for the overall population and 12% for the irinotecan-failure population. The median durations of response were 6.5 and 6.7 months, respectively.

ERBITUX was studied as a single agent in a multicenter, open-label, single-arm clinical trial in patients with EGFR-expressing metastatic colorectal cancer who progressed following an irinotecan-containing regimen. Of 57 patients enrolled, 28 patients had documented progression to irinotecan. The overall response rate was 9% for the all-treated group and 14% for the irinotecan-failure group. The median times to progression were 1.4 and 1.3 months, respectively. The median duration of response was 4.2 months for both groups.

EGFR EXPRESSION AND RESPONSE

Patients enrolled in the clinical studies were required to have immunohistochemical evidence of positive EGFR expression. Primary tumor or tumor from a metastatic site was tested with the DakoCytomation EGFR pharmDx™ test kit. Specimens were scored based on the percentage of cells expressing EGFR and intensity (barely/faint, weak to moderate, and strong). Response rate did not correlate with either the percentage of positive cells or the intensity of EGFR expression.

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