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 receptorassociated 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 Ras proteins,
but in cells with activating Ras somatic mutations, the resulting mutant Ras proteins
are continuously active regardless 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 EUapproved cetuximab used in
Studies 2 and 4 based on a population pharmacokinetic analysis [see Clinical
Studies].
A drug interaction study was performed in which Erbitux
was administered in combination with irinotecan. There was no evidence of any
pharmacokinetic interactions between Erbitux and irinotecan.
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
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 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. Sixtyfour 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
 |
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 Wild-type,
EGFR-expressing, 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 wild-type tumors and 403 (37%)
patients had K-Ras mutant 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 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 followup (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 wild-type
tumors. There is no evidence of effectiveness in the subgroup of patients with K-Ras
mutant tumors.
Table 8: Clinical Efficacy in First-line
EGFR-expressing, Metastatic Colorectal Cancer (All Randomized and K-Ras Status)
|
All Randomized |
K-Ras Wild-type |
K-Ras Mutant |
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.
b Post-hoc updated OS analysis, results based on an additional 162
events. |
Figure 2: Kaplan-Meier Curve for Overall Survival in
the K-Ras Wild-type Population in Study 4
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 wild-type tumors and 208 (46%) patients
had K-Ras mutant 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 Wild-type |
K-Ras Mutant |
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) (95% CI) |
6.1
(5.4, 6.7) |
4.6
(4.2, 4.9) |
8.6
(7.0, 10.3) |
5.0
(4.3, 5.7) |
4.8
(3.9, 5.6) |
4.6
(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 Wild-type Metastatic Colorectal Cancer in Study 5
 |
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 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 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.