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This information is intended for US healthcare professionals only.
An overall survival advantage was maintained at 3 and 5 years.
ERBITUX® + radiation therapy (RT) vs RT alone:
Overall survival rates at 3 and 5 years
Erbitux + RT chart
1.6 years improvement in median overall survival3
10% absolute improvement in 3-year survival rate vs RT alone1
9.2% absolute improvement in 5-year survival rate vs RT alone2
Significant improvement in locoregional control1,3
Primary endpoint: Median duration of locoregional control (N=424). ERBITUX + RT (n=211) improved median duration of locoregional control by 0.8 years vs RT alone (n=213) (2.0 years vs 1.2 years, respectively; HR=0.68 [95% CI: 0.52-0.89]; P=0.005).
CI=confidence interval; HR=hazard ratio.
Bonner study design—A multicenter, phase III trial of ERBITUX + RT1,3
This study was an open-label, randomized (1:1), multicenter, controlled clinical trial that compared ERBITUX + RT vs RT alone in untreated patients with locally or regionally advanced SCCHN
Primary endpoint was duration of locoregional control
Secondary endpoint included overall survival. A post-RT neck dissection was recommended for patients with >N1 neck disease. Patients were stratified according to T1-3 vs T4, N0 vs N+, RT fractionation, and KPS (60%-80% vs 90%-100%)
Bonner study graph
EGFR=epidermal growth factor receptor; KPS=Karnofsky performance status.
Bonner study: Most common adverse reactions3
Adverse Reactions chart
* Includes cases also reported as infusion reaction.
Infusion reaction is defined as any reaction described at any time during the clinical study as "allergic reaction" or "anaphylactoid reaction," or any reaction occurring on the first day of dosing described as "allergic reaction," "anaphylactoid reaction," "fever," "chills," "chills and fever," or "dyspnea."
Based on laboratory measurements, not on reported adverse reactions, the number of subjects with tested samples varied from 205-206 for ERBITUX plus radiation arm; 209-210 for radiation alone.
Discontinuation rate1
6% of patients (13/208) discontinued ERBITUX due to any adverse reaction in the Bonner study
ERBITUX-related adverse reactions leading to discontinuation included hypersensitivity reactions, grade 3 acneiform rash, and unspecified reason
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Full Prescribing
Information
Important Safety
Information Including
Boxed Warnings
ERBITUX.com/hcp
INDICATION
Head and neck cancer
ERBITUX® (cetuximab), in combination with radiation therapy, is indicated for the initial treatment of locally or regionally advanced squamous cell carcinoma of the head and neck (SCCHN)
WARNING:
SERIOUS INFUSION REACTIONS and CARDIOPULMONARY ARREST
Infusion Reactions:
Serious infusion reactions occurred with the administration of ERBITUX in approximately 3% of patients in clinical trials, with fatal outcome reported in less than 1 in 1000. Immediately interrupt and permanently discontinue ERBITUX infusion for serious infusion reactions.
Cardiopulmonary Arrest:
Cardiopulmonary arrest and/or sudden death occurred in 2% of patients with squamous cell carcinoma of the head and neck treated in a clinical trial with ERBITUX and radiation therapy and in 3% of patients with squamous cell carcinoma of the head and neck treated in a clinical trial with European Union (EU)-approved cetuximab in combination with platinum-based therapy with 5-fluorouracil (5-FU). Closely monitor serum electrolytes, including serum magnesium, potassium, and calcium, during and after ERBITUX administration.
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References
1.  Bonner JA, et al. N Engl J Med. 2006;354(6):567-578.
2.  Bonner JA, et al. Lancet Oncol. 2010;11(1):21-28.
3.  ERBITUX (cetuximab) [package insert]. Indianapolis, IN: Eli Lilly and Company, its subsidiaries or affiliates.
IMPORTANT SAFETY INFORMATION FOR ERBITUX
WARNING: SERIOUS INFUSION REACTIONS and CARDIOPULMONARY ARREST
Infusion Reactions:
Grade 3/4 infusion reactions occurred in approximately 3% of patients receiving ERBITUX® (cetuximab) in clinical trials, with fatal outcome reported in less than 1 in 1000
  Serious infusion reactions, requiring medical intervention and immediate, permanent discontinuation of ERBITUX, included rapid onset of airway obstruction (bronchospasm, stridor, hoarseness), hypotension, shock, loss of consciousness, myocardial infarction, and/or cardiac arrest
  Immediately interrupt and permanently discontinue ERBITUX infusion for serious infusion reactions
Approximately 90% of the severe infusion reactions were associated with the first infusion of ERBITUX despite premedication with antihistamines
  Caution must be exercised with every ERBITUX infusion, as there were patients who experienced their first severe infusion reaction during later infusions
  Monitor patients for 1 hour following ERBITUX infusions in a setting with resuscitation equipment and other agents necessary to treat anaphylaxis (eg, epinephrine, corticosteroids, intravenous antihistamines, bronchodilators, and oxygen). Longer observation periods may be required in patients who require treatment for infusion reactions
Cardiopulmonary Arrest:
Cardiopulmonary arrest and/or sudden death occurred in 4 (2%) of 208 patients with squamous cell carcinoma of the head and neck treated with radiation therapy and ERBITUX, as compared to none of 212 patients treated with radiation therapy alone. In 3 patients with prior history of coronary artery disease, death occurred 27, 32, and 43 days after the last dose of ERBITUX. One patient with no prior history of coronary artery disease died one day after the last dose of ERBITUX. Fatal cardiac disorders and/or sudden death occurred in 7 (3%) of the 219 patients with squamous cell carcinoma of the head and neck treated with platinum-based therapy with 5-fluorouracil (5-FU) and European Union (EU)-approved cetuximab as compared to 4 (2%) of the 215 patients treated with chemotherapy alone. Five of these 7 patients in the chemotherapy plus cetuximab arm received concomitant cisplatin and 2 patients received concomitant carboplatin. All 4 patients in the chemotherapy-alone arm received cisplatin
  Carefully consider the use of ERBITUX in combination with radiation therapy or platinum-based therapy with 5-FU in head and neck cancer patients with a history of coronary artery disease, congestive heart failure, or arrhythmias in light of these risks
  Closely monitor serum electrolytes, including serum magnesium, potassium, and calcium during and after ERBITUX therapy
Pulmonary Toxicity
Interstitial lung disease (ILD), which was fatal in one case, occurred in 4 of 1570 (<0.5%) patients receiving ERBITUX in Studies 1, 3, and 6, as well as other studies, in colorectal cancer and head and neck cancer. Interrupt ERBITUX for acute onset or worsening of pulmonary symptoms. Permanently discontinue ERBITUX for confirmed ILD
Dermatologic Toxicities
In clinical studies of ERBITUX, dermatologic toxicities, including acneiform rash, skin drying and fissuring, paronychial inflammation, infectious sequelae (eg, S. aureus sepsis, abscess formation, cellulitis, blepharitis, conjunctivitis, keratitis/ulcerative keratitis with decreased visual acuity, cheilitis), and hypertrichosis, occurred in patients receiving ERBITUX therapy.
  Acneiform rash occurred in 76-88% of 1373 patients receiving ERBITUX in Studies 1, 3, 5, and 6. Severe acneiform rash occurred in 1-17% of patients. Acneiform rash usually developed within the first 2 weeks of therapy and resolved in a majority of the patients after cessation of treatment, although in nearly half, the event continued beyond 28 days
  Life-threatening and fatal bullous mucocutaneous disease with blisters, erosions, and skin sloughing has also been observed in patients treated with ERBITUX. It could not be determined whether these mucocutaneous adverse reactions were directly related to EGFR inhibition or to idiosyncratic immune-related effects (eg, Stevens-Johnson syndrome or toxic epidermal necrolysis)
  Monitor patients receiving ERBITUX for dermatologic toxicities and infectious sequelae
  Sun exposure may exacerbate these effects
ERBITUX Plus Radiation Therapy and Cisplatin
In a controlled study, 940 patients with locally advanced SCCHN were randomized 1:1 to receive either ERBITUX in combination with radiation therapy and cisplatin or radiation therapy and cisplatin alone. The addition of ERBITUX resulted in an increase in the incidence of Grade 3-4 mucositis, radiation recall syndrome, acneiform rash, cardiac events, and electrolyte disturbances compared to radiation and cisplatin alone
Adverse reactions with fatal outcome were reported in 20 patients (4.4%) in the ERBITUX combination arm and 14 patients (3.0%) in the control arm
Nine patients in the ERBITUX arm (2.0%) experienced myocardial ischemia compared to 4 patients (0.9%) in the control arm
The addition of ERBITUX to radiation and cisplatin did not improve progression-free survival (the primary endpoint)
Electrolyte Depletion
Hypomagnesemia occurred in 55% of 365 patients receiving ERBITUX in Study 5 and two other clinical trials in colorectal cancer and head and neck cancer, respectively, and was severe (NCI CTC grades 3 & 4) in 6-17%. In Study 2 the addition of EU-approved cetuximab to cisplatin and 5-FU resulted in an increased incidence of hypomagnesemia (14% vs 6%) and of grade 3-4 hypomagnesemia (7% vs 2%) compared to cisplatin and 5-FU alone. In contrast, the incidences of hypomagnesemia were similar for those who received cetuximab, carboplatin, and 5-FU compared to carboplatin and 5-FU (4% vs 4%). No patient experienced grade 3-4 hypomagnesemia in either arm in the carboplatin subgroup. The onset of hypomagnesemia and accompanying electrolyte abnormalities occurred days to months after initiation of ERBITUX therapy
  Monitor patients periodically for hypomagnesemia, hypocalcemia, and hypokalemia, during, and for at least 8 weeks following the completion of, ERBITUX therapy
  Replete electrolytes as necessary
Late Radiation Toxicities
The overall incidence of late radiation toxicities (any grade) was higher with ERBITUX in combination with radiation therapy compared with radiation therapy alone. The following sites were affected: salivary glands (65% vs 56%), larynx (52% vs 36%), subcutaneous tissue (49% vs 45%), mucous membranes (48% vs 39%), esophagus (44% vs 35%), and skin (42% vs 33%) in the ERBITUX and radiation versus radiation-alone arms, respectively
  The incidence of grade 3 or 4 late radiation toxicities was similar between the radiation therapy alone and the ERBITUX plus radiation therapy arms
Pregnancy and Nursing
In women of childbearing potential and men, appropriate contraceptive measures must be used during treatment with ERBITUX and for 6 months following the last dose of ERBITUX. ERBITUX may be transmitted from the mother to the developing fetus, and has the potential to cause fetal harm when administered to pregnant women. ERBITUX should only be used during pregnancy if the potential benefit justifies the potential risk to the fetus
It is not known whether ERBITUX is secreted in human milk. IgG antibodies, such as ERBITUX, can be excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from ERBITUX, a decision should be made whether to discontinue nursing or to discontinue ERBITUX, taking into account the importance of ERBITUX to the mother. If nursing is interrupted, based on the mean half-life of cetuximab, nursing should not be resumed earlier than 60 days following the last dose of ERBITUX
Adverse Reactions
The most serious adverse reactions associated with ERBITUX are infusion reactions, cardiopulmonary arrest, dermatologic toxicity and radiation dermatitis, sepsis, renal failure, interstitial lung disease, and pulmonary embolus
The most common adverse reactions associated with ERBITUX (incidence ≥25%) across all studies were cutaneous adverse reactions (including rash, pruritus, and nail changes), headache, diarrhea, and infection
The most frequent adverse reactions seen in patients with carcinomas of the head and neck receiving ERBITUX in combination with radiation therapy (n=208) versus radiation alone (n=212) (incidence ≥50%) were acneiform rash (87% vs 10%), radiation dermatitis (86% vs 90%), weight loss (84% vs 72%), and asthenia (56% vs 49%). The most common grade 3/4 adverse reactions for ERBITUX in combination with radiation therapy (≥10%) versus radiation alone included: radiation dermatitis (23% vs 18%), acneiform rash (17% vs 1%), and weight loss (11% vs 7%)
The most frequent adverse reactions seen in patients with carcinomas of the head and neck receiving EU-approved cetuximab in combination with platinum-based therapy with 5-FU (CT) (n=219) versus CT alone (n=215) (incidence ≥40%) were acneiform rash (70% vs 2%), nausea (54% vs 47%), and infection (44% vs 27%). The most common grade 3/4 adverse reactions for cetuximab in combination with CT (≥10%) versus CT alone included: infection (11% vs 8%). Since U.S.-licensed ERBITUX provides approximately 22% higher exposure relative to the EU-approved cetuximab, the data provided above may underestimate the incidence and severity of adverse reactions anticipated with ERBITUX for this indication. However, the tolerability of the recommended dose is supported by safety data from additional studies of ERBITUX
Please see full Prescribing Information for ERBITUX, including Boxed Warnings regarding infusion reactions and cardiopulmonary arrest.
CE HCP ISI_SCCHN 17JUN2015
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PP-CE-US-0416 10/2017 © Lilly USA, LLC 2017. All rights reserved. ERBITUX® is a registered trademark owned or licensed by Eli Lilly and Company, its subsidiaries, or affiliates.
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