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Erbitux

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Erbitux

CLINICAL PHARMACOLOGY

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 K-Ras protein. However, in cells with activating K-Ras somatic mutations, the mutant K-Ras 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 anti-tumor 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.

Pharmacodynamics

Effects on Electrocardiogram (ECG)

The effect of cetuximab on QT interval was evaluated in an open-label, single-arm, monotherapy trial in 37 subjects with advanced malignancies who received an initial dose of 400 mg/m², followed by weekly infusions of 250 mg/m² for a total of 5 weeks. No large changes in the mean QT interval of > 20 ms from baseline were detected in the trial based on the Fridericia correction method. A small increase in the mean QTc interval of < 10 ms cannot be excluded because of the limitations in the trial design.

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.

Erbitux had an approximately 22% (90% confidence interval; 6%, 38%) higher systemic exposure relative to the EU-approved cetuximab used in Studies 2 and 4 based on a population pharmacokinetic analysis. [See Clinical Studies.]

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

Studies 2 and 4 were conducted outside the U.S. using an EU-approved cetuximab as the clinical trial material. Erbitux provides approximately 22% higher exposure relative to the EU-approved cetuximab used in Studies 2 and 4; these pharmacokinetic data, together with the results of Studies 2, 4, and other clinical trial data establish the efficacy of Erbitux at the recommended dose in SCCHN and mCRC [see CLINICAL PHARMACOLOGY].

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 twicedaily).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 U.S. 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 6.

Table 6: Study 1: Clinical Efficacy in Locoregionally Advanced SCCHN

  Erbitux + Radiation
(n=211)
Radiation Alone
(n=213)
Hazard Ratio (95% CIa) Stratified Log-rank p-value
Locoregional Control
  Median duration (months) 24.4 14.9 0.68
(0.52-0.89)
0.005
Overall Survival
  Median duration (months) 49.0 29.3 0.74
(0.57-0.97)
0.03

a CI = confidence interval

Study 2 was an open-label, randomized, multicenter, controlled trial of 442 patients with recurrent locoregional disease or metastatic SCCHN.

Patients with no prior therapy for recurrent locoregional disease or metastatic SCCHN were randomized (1:1) to receive EU-approved cetuximab plus cisplatin or carboplatin and 5-FU, or cisplatin or carboplatin and 5-FU alone. Choice of cisplatin or carboplatin was at the discretion of the treating physician. Stratification factors were Karnofsky performance status ( < 80 versus ≥ 80) and previous chemotherapy. Cisplatin (100 mg/m², Day 1) or carboplatin (AUC 5, Day 1) plus intravenous 5-FU (1000 mg/m²/day, Days 1-4) were administered every 3 weeks (1 cycle) for a maximum of 6 cycles in the absence of disease progression or unacceptable toxicity. Cetuximab was administered at a 400 mg/m² initial dose, followed by a 250 mg/m² weekly dose in combination with chemotherapy. Patients demonstrating at least stable disease on cetuximab in combination with chemotherapy were to continue cetuximab monotherapy at 250 mg/m² weekly, in the absence of disease progression or unacceptable toxicity after completion of 6 planned courses of platinum-based therapy. For patients where treatment was delayed because of the toxic effects of chemotherapy, weekly cetuximab was continued. If chemotherapy was discontinued for toxicity, cetuximab could be continued as monotherapy until disease progression or unacceptable toxicity.

Of the 442 randomized patients, the median age was 57 years, 90% were male, 98% were Caucasian, and 88% had baseline Karnofsky performance status ≥ 80. Thirty-four percent of patients had oropharyngeal, 25% laryngeal, 20% oral cavity, and 14% hypopharyngeal primary tumors. Fifty-three percent of patients had recurrent locoregional disease only and 47% had metastatic disease. Fifty-eight percent had AJCC Stage IV disease and 21% had Stage III disease. Sixty-four percent of patients received cisplatin therapy and 34% received carboplatin as initial therapy. Approximately fifteen percent of the patients in the cisplatin alone arm switched to carboplatin during the treatment period.

The main outcome measure of this trial was overall survival. Results are presented in Table 7 and Figure 1.

Table 7: Study 2: Clinical Efficacy in Recurrent Locoregional Disease or Metastatic SCCHN

  EU-Approved Cetuximab + Platinum-based Therapy + 5-FU
(n=222)
Platinum-based Therapy + 5-FU
(n=220)
Hazard Ratio (95% CIa) Stratified Log-rank p-value
Overall Survival
Median duration (months) 10.1 7.4 0.80 (0.64, 0.98) 0.034
Progression-free Survival
Median duration (months) 5.5 3.3 0.57 (0.46, 0.72) < 0.0001
  EU-Approved Cetuximab + Platinum-based Therapy + 5-FU
(n=222)
Platinum-based Therapy + 5-FU
(n=220)
Odds Ratio (95% CIa) CMHb test p-value
Objective Response Rate 35.6% 19.5% 2.33 (1.50, 3.60) 0.0001
a CI = confidence interval
b CMH = Cochran-Mantel-Haenszel

Figure 1: Kaplan-Meier Curve for Overall Survival in Patients with Recurrent Locoregional Disease or Metastatic Squamous Cell Carcinoma of the Head and Neck

Kaplan-Meier Curve for Overall Survival - Illustration

In exploratory subgroup analyses of Study 2 by initial platinum therapy (cisplatin or carboplatin), for patients (N=284) receiving cetuximab plus cisplatin with 5-FU compared to cisplatin with 5-FU alone, the difference in median overall survival was 3.3 months (10.6 versus 7.3 months, respectively; HR 0.71; 95% CI 0.54, 0.93). The difference in median progression-free survival was 2.1 months (5.6 versus 3.5 months, respectively; HR 0.55; 95% CI 0.41, 0.73). The objective response rate was 39% and 23%, respectively (OR 2.18; 95% CI 1.29, 3.69). For patients (N=149) receiving cetuximab plus carboplatin with 5-FU compared to carboplatin with 5-FU alone, the difference in median overall survival was 1.4 months (9.7 versus 8.3 months; HR 0.99; 95% CI 0.69, 1.43). The difference in median progression-free survival was 1.7 months (4.8 versus 3.1 months, respectively; HR 0.61; 95% CI 0.42, 0.89). The objective response rate was 30% and 15%, respectively (OR 2.45; 95% CI 1.10, 5.46).

Study 3 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 K-Ras Mutation-negative (Wild-type), EGFRexpressing, Metastatic Colorectal Cancer

Study 4 was a randomized, open-label, multicenter, study of 1217 patients with EGFR-expressing, metastatic colorectal cancer. Patients were randomized (1:1) to receive either EU-approved cetuximab in combination with FOLFIRI or FOLFIRI alone as first-line treatment. Stratification factors were Eastern Cooperative Oncology Group (ECOG) performance status (0 and 1 versus 2) and region (sites in Western Europe versus Eastern Europe versus other).

FOLFIRI regimen included 14-day cycles of irinotecan (180 mg/m² administered intravenously on Day 1), folinic acid (400 mg/m² [racemic] or 200 mg/m² [L-form] administered intravenously on Day 1), and 5-FU (400 mg/m² bolus on Day 1 followed by 2400 mg/m² as a 46-hour continuous infusion). Cetuximab was administered as a 400 mg/m² initial dose on Day 1, Week 1, followed by 250 mg/m² weekly administered 1 hour prior to chemotherapy. Study treatment continued until disease progression or unacceptable toxicity occurred.

Of the 1217 randomized patients, the median age was 61 years, 60% were male, 86% were Caucasian, and 96% had a baseline ECOG performance status 0-1, 60% had primary tumor localized in colon, 84% had 1-2 metastatic sites and 20% had received prior adjuvant and/or neoadjuvant chemotherapy. Demographics and baseline characteristics were similar between study arms.

K-Ras mutation status was available for 1079/1217 (89%) of the patients: 676 (63%) patients had K-Ras mutation-negative (wild-type) tumors and 403 (37%) patients had K-Ras mutation-positive tumors where testing assessed for the following somatic mutations in codons 12 and 13 (exon 2): G12A, G12D, G12R, G12C, G12S, G12V, G13D [see WARNINGS AND PRECAUTIONS].

Baseline characteristics and demographics in the K-Ras mutation-negative (wild-type) subset were similar to that seen in the overall population [see WARNINGS AND PRECAUTIONS].

The main outcome measure of this trial was progression-free survival assessed by an independent review committee (IRC). Overall survival and response rate were also assessed. A statistically significant improvement in PFS was observed for the cetuximab plus FOLFIRI arm compared with the FOLFIRI arm (median PFS 8.9 vs. 8.1 months, HR 0.85 [95% CI 0.74, 0.99], p-value=0.036). Overall survival was not significantly different at the planned, final analysis based on 838 events [HR=0.93, 95% CI (0.8, 1.1), p-value 0.327].

Results of the planned PFS and ORR analysis in all randomized patients and post-hoc PFS and ORR analysis in subgroups of patients defined by K-Ras mutation status, and post-hoc analysis of updated OS based on additional follow-up (1000 events) in all randomized patients and in subgroups of patients defined by K-Ras mutation status are presented in Table 8 and Figure 2. The treatment effect in the all-randomized population for PFS was driven by treatment effects limited to patients who have K-Ras mutation negative (wild-type) tumors. There is no evidence of effectiveness in the subgroup of patients with K-Ras mutation-positive tumors.

Table 8: Clinical Efficacy in First-line EGFR-expressing, Metastatic Colorectal Cancer (All Randomized and K-Ras Status)

  All Randomized K-Ras Mutation-negative (Wild-type) K-Ras Mutation-positive
EU-Approved Cetuximab plus FOLFIRI
(n=608)
FOLFIRI
(n=609)
EU-Approved Cetuximab plus FOLFIRI
(n=320)
FOLFIRI
(n=356)
EU-Approved Cetuximab plus FOLFIRI
(n=216)
FOLFIRI
(n=187)
Progression-Free Survival
Number of Events (%) 343 (56) 371 (61) 165(52) 214 (60) 138 (64) 112 (60)
Median (months) (95% CI) 8.9 (8.0, 9.4) 8.1 (7.6, 8.8) 9.5 (8.9, 11.1) 8.1 (7.4, 9.2) 7.5 (6.7, 8.7) 8.2 (7.4, 9.2)
HR (95% CI) 0.85 (0.74, 0.99) 0.70 (0.57, 0.86) 1.13 (0.88, 1.46)
p-valuea 0.0358
Overall Survivalb
Number of Events (%) 491 (81) 509 (84) 244 (76) 292 (82) 189 (88) 159 (85)
Median (months) (95% CI) 19.6 (18, 21) 18.5 (17, 20) 23.5 (21, 26) 19.5 (17, 21) 16.0 (15, 18) 16.7 (15, 19)
HR (95% CI) 0.88 (0.78, 1.0) 0.80 (0.67, 0.94) 1.04 (0.84, 1.29)
Objective Response Rate
ORR (95% CI) 46% (42, 50) 38% (34, 42) 57% (51, 62) 39% (34, 44) 31% (25, 38) 35% (28, 43)
a Based on the Stratified Log-rank test.
bPost-hoc updated OS analysis, results based on an additional 162 events.

Figure 2: Kaplan-Meier Curve for Overall Survival in the K-Ras Mutation-negative (Wild-type) Population in Study 4

Kaplan-Meier Curve for Overall Survival in the K-Ras Mutation-negative - Illustration

Study 5 was a multicenter, open-label, randomized, clinical trial conducted in 572 patients with EGFR-expressing, previously treated, recurrent 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. Demographics and baseline characteristics were similar between study arms. All patients were to have received and progressed on prior therapy including an irinotecan-containing regimen and an oxaliplatin-containing regimen.

K-Ras status was available for 453/572 (79%) of the patients: 245 (54%) patients had K-Ras mutation-negative (wild-type) tumors and 208 (46%) patients had K-Ras mutationpositive tumors where testing assessed for the following somatic mutations in codons 12 and 13 (exon 2): G12A, G12D, G12R, G12C, G12S, G12V, G13D [see WARNINGS AND PRECAUTIONS].

The main outcome measure of the study was overall survival. Results are presented in Table 9 and Figure 3.

Table 9: Overall Survival in Previously Treated EGFR-expressing, Metastatic Colorectal Cancer (All Randomized and K-Ras Status)

  All Randomized K-Ras Mutation-negative (Wild-type) K-Ras Mutation-positive
Erbitux plus BSC
(N=287)
BSC
(N=285)
Erbitux plus BSC
(N=117)
BSC
(N=128)
Erbitux plus BSC
(N=108)
BSC
(N=100)
Median (months) 6.1 4.6 8.6 5.0 4.8 4.6
(95% CI) (5.4, 6.7) (4.2, 4.9) (7.0, 10.3) (4.3, 5.7) (3.9, 5.6) (3.6, 4.9)
HR 0.77 0.63 0.91
(95% CI) (0.64, 0.92) (0.47, 0.84) (0.67, 1.24)
p-valuea 0.0046
a Based on the Stratified Log-rank test.

Figure 3: Kaplan-Meier Curve for Overall Survival in Patients with K-Ras Mutation-negative (Wild-type) Metastatic Colorectal Cancer in Study 5

Kaplan-Meier Curve for Overall Survival in Patients with K-Ras Mutation-negative (Wild-type) Metastatic Colorectal Cancer in Study 5 - Illustration

Study 6 was a multicenter, clinical trial conducted in 329 patients with EGFR-expressing recurrent mCRC. Tumor specimens were not available for testing for K-Ras mutation status. 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 32 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 pre-specified 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 pre-defined subsets in both the combination arm and monotherapy arm of the study.

Last reviewed on RxList: 3/25/2013
This monograph has been modified to include the generic and brand name in many instances.

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