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CRYSTAL study and post hoc analyses: Efficacy results* in KRAS and RAS
wild-type mCRC1-3

Key efficacy endpoints* in KRAS and RAS wild-type mCRC subpopulations

CRYSTAL=Cetuximab combined with iRinotecan in first-line therapY for metaSTatic colorectAL cancer

CRYSTAL regimen=EU-approved cetuximab + FOLFIRI

Table showing efficacy results from the CRYSTAL study KRAS and RAS wild-type post-hoc analyses

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  • The main outcome measure for the study was progression-free survival in the all-randomized patient population1
  • In all-randomized patients, 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=0.327)1
  • Limitations of the post hoc analysis data: Only 65% of patients with KRAS wild-type tumors were evaluable for RAS status. RAS wild-type subpopulation data presented may not be representative of the label population
  • The CRYSTAL study was not adequately powered, nor error-controlled, for subgroup analyses. Treatment differences observed in these subgroups cannot be regarded as statistically significant. The analyses described here were exploratory
  • Limitation of Use: ERBITUX is not indicated for treatment of RAS-mutant colorectal cancer or when the results of the RAS mutation tests are unknown

*Post hoc updated overall survival analysis based on an additional 162 events.1

†Objective response=complete response + partial response; tumor size reduction ≥50% (modified WHO criteria).2-4

‡Based on the stratified log-rank test.1

CI=confidence interval; EU=European Union; FOLFIRI=irinotecan, 5-fluorouracil, and leucovorin; HR=hazard ratio; WHO=World Health Organization.

View study design View safety profile View NCCN recommendation

INDICATIONS

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)
  • ERBITUX is indicated in combination with platinum-based therapy with 5-FU for the first-line treatment of patients with recurrent locoregional disease or metastatic squamous cell carcinoma of the head and neck
  • ERBITUX, as a single agent, is indicated for the treatment of patients with recurrent or metastatic squamous cell carcinoma of the head and neck for whom prior platinum-based therapy has failed

Metastatic Colorectal Cancer

ERBITUX is indicated for the treatment of KRAS wild-type, epidermal growth factor receptor (EGFR)-expressing, metastatic colorectal cancer (mCRC) as determined by FDA-approved tests for this use:

  • In combination with FOLFIRI (irinotecan, 5-fluorouracil, leucovorin) for first-line treatment
  • In combination with irinotecan in patients who are refractory to irinotecan-based chemotherapy
  • As a single agent in patients who have failed oxaliplatin- and irinotecan-based chemotherapy or who are intolerant to irinotecan

Limitation of Use: ERBITUX is not indicated for treatment of RAS-mutant colorectal cancer or when the results of the RAS mutation tests are unknown.

INDICATIONS

Head and Neck Cancer

  • ERBITUX® (cetuximab), in combination with radiation therapy, is approved for the initial treatment of a certain type of locally or regionally advanced head and neck cancer
  • ERBITUX, in combination with platinum-based chemotherapy with 5-fluorouracil, is approved for the initial treatment of patients with a certain type of head and neck cancer whose tumor has returned in the same location or spread to other parts of the body
  • ERBITUX is also approved for use alone to treat patients with a certain type of head and neck cancer whose tumor has returned in the same location or spread to other parts of the body and whose disease has progressed following platinum-based chemotherapy

Metastatic Colorectal Cancer

ERBITUX is approved for the treatment of certain patients who have colorectal cancer that has spread to other parts of the body. Only patients whose tumors are KRAS wild-type (which means they have a KRAS mutation-negative gene), and whose tumors have a protein called epidermal growth factor receptor (EGFR), should receive ERBITUX. FDA-approved tests are used to determine if tumors have these particular traits. Treatment with ERBITUX is given in the following three ways:

  • In combination with FOLFIRI (irinotecan, 5-fluorouracil, leucovorin) for patients who are being treated for this type of cancer for the first time
  • In combination with another chemotherapy drug, irinotecan, for patients whose disease has progressed after receiving chemotherapy with irinotecan
  • As a single agent:
    • For patients whose disease has progressed after receiving both irinotecan and oxaliplatin
    • For patients who are unable to tolerate chemotherapy with irinotecan

ERBITUX is not approved to treat colorectal cancer in patients whose tumors have mutations in genes called RAS (often called "RAS mutant"), or in patients for whom the mutational status of the genes is not known.

ERBITUX is available by prescription only.

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WARNING: SERIOUS INFUSION REACTIONS and CARDIOPULMONARY ARREST

Infusion Reactions:

Serious infusion reactions occurred with the administration of ERBITUX® (cetuximab) 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.

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

WARNING: ALLERGIC REACTIONS and HEART ATTACK

Allergic Reactions:

  • Severe allergic reactions due to ERBITUX® (cetuximab) therapy have occurred in 42 of 1373 patients (3%) receiving ERBITUX during clinical studies, resulting in death in less than 1 in 1000 patients
    • Symptoms can include trouble with breathing (including tightening of the airways, wheezing, or hoarseness), low blood pressure, shock, loss of consciousness, and/or heart attack. Report these signs and symptoms of infusion reactions, as well as fever, chills, or breathing problems to your doctor or nurse
    • Approximately 90% of the severe allergic reactions occurred with the first dose of ERBITUX, although some patients experienced their first severe allergic reaction during a subsequent dose of ERBITUX
    • Your doctor or nurse should watch you closely for these symptoms during treatment and may need to stop therapy in the event of an allergic reaction
    • Severe allergic reactions require that treatment with ERBITUX be stopped immediately and not started again

Heart Attack:

  • Heart attack and/or sudden death occurred in 4 of 208 patients (2%) with head and neck cancer treated with radiation therapy and ERBITUX, as compared to none of 212 patients treated with radiation therapy alone
  • Heart problems resulting in death and/or sudden death occurred in 7 of 219 patients (3%) with head and neck cancer treated with platinum-based chemotherapy with 5-fluorouracil and cetuximab compared to 4 of 215 patients (2%) treated with chemotherapy alone, based on a study conducted in Europe using European cetuximab
  • Notify your doctor if you have a history of any heart disease
Please see additional Important Safety Information below.
View All

Extended median overall survival (OS) in the KRAS wild-type subpopulation1

CRYSTAL regimen vs FOLFIRI alone

Post hoc analysis: OS in the KRAS wild-type subpopulation (n=676)

CRYSTAL study median overall survival KM curve showing 23.5 months for the CRYSTAL regimen vs 19.5 months with FOLFIRI alone in patients with KRAS wild-type mCRC

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  • 2-year survival rates of patients: 45% for the CRYSTAL regimen vs 37% for FOLFIRI alone*
  • 3-year survival rates of patients: 26% for the CRYSTAL regimen vs 18% for FOLFIRI alone†

*2-year survival rate for CET + CT: (144/320) x 100% = 45%; for CT: (132/356) x 100% = 37%.

†3-year survival rate for CET + CT: (82/320) x 100% = 26%; for CT: (64/356) x 100% = 18%.

CRYSTAL RAS wild-type post hoc analysis: Median OS in mCRC3

CRYSTAL regimen vs FOLFIRI alone

Median OS in the RAS wild-type subpopulation of the KRAS wild-type subgroup (n=367)

CRYSTAL study post hoc analysis median overall survival KM curve showing 28.4 months for the CRYSTAL regimen vs 20.2 months with FOLFIRI alone in patients with RAS wild-type mCRC

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Limitations of the post hoc analysis data: Only 65% of patients with KRAS wild-type tumors were evaluable for RAS status. RAS wild-type subpopulation data presented may not be representative of the label population.

The CRYSTAL study was not adequately powered, nor error-controlled, for subgroup analyses. Treatment differences observed in these subgroups cannot be regarded as statistically significant. The analyses described here were exploratory.

CET=EU-approved cetuximab; CT=FOLFIRI.

View study design View safety profile View NCCN recommendation

Nearly 6 out of 10 patients in the KRAS wild-type subpopulation had at least a 50% reduction in tumor size1

CRYSTAL regimen vs FOLFIRI alone

Post hoc analysis: Objective response rate (ORR)* in the KRAS wild-type subpopulation (n=676)

Bar chart showing a reduction in tumor size ≥50% in 57% of patients with KRAS wild-type mCRC treated with the CRYSTAL regimen vs 39% of patients treated with FOLFIRI alone

In the CRYSTAL study and post hoc analysis, ORRs were evaluated utilizing modified WHO criteria.†2-4

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CRYSTAL RAS wild-type post hoc analysis: Tumor response rate* in mCRC3

CRYSTAL regimen vs FOLFIRI alone

ORR* in the RAS wild-type subpopulation of the KRAS wild-type subgroup (n=367)

CRYSTAL study post hoc analysis bar chart showing a reduction in tumor size ≥50% in 66.3% of patients with RAS wild-type mCRC treated with the CRYSTAL regimen vs 38.6% of patients treated with FOLFIRI alone

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Limitations of the post hoc analysis data: Only 65% of patients with KRAS wild-type tumors were evaluable for RAS status. RAS wild-type subpopulation data presented may not be representative of the label population.

The CRYSTAL study was not adequately powered, nor error-controlled, for subgroup analyses. Treatment differences observed in these subgroups cannot be regarded as statistically significant. The analyses described here were exploratory.

*Objective response=complete response + partial response; tumor size reduction ≥50% (modified WHO criteria).2-4

†Criteria for ORRs4

  • The ORR is the sum of the rate of partial response and the rate of complete response
  • Partial response: ≥50% decrease in the sum of the products of the longest diameter and the greatest perpendicular diameter of all index lesions compared to baseline, by 2 observations not less than 4 weeks apart, and no evidence of progressive disease
  • Complete response: disappearance of all measurable lesions by 2 observations no less than 4 weeks apart, without the appearance of any new lesions
View study design View safety profile View NCCN recommendation

CRYSTAL study design and post hoc analyses1-3

CRYSTAL was a phase III, open-label, randomized, multicenter study (N=1217) conducted outside the US that used European Union (EU)-approved cetuximab as the clinical trial material for EGFR-expressing metastatic colorectal cancer (mCRC).

KRAS subpopulation in the CRYSTAL study

CRYSTAL study design diagram of KRAS wild-type mCRC post hoc analysis

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  • ERBITUX provides approximately 22% higher exposure relative to the EU-approved cetuximab; these pharmacokinetic data, together with the results of this trial and other clinical trial data, establish the efficacy of ERBITUX at the recommended dose in combination with FOLFIRI for first-line treatment of KRAS wild-type mCRC
  • Patients were randomized (1:1) to receive either EU-approved cetuximab in combination with FOLFIRI* (n=608) (CRYSTAL regimen) or FOLFIRI alone* (n=609) as first-line treatment until disease progression or unacceptable toxicity occurred
  • The main outcome measure was progression-free survival in all randomized patients; secondary endpoints were overall survival and response rate. Progression-free survival was derived from an assessment by an independent review committee (IRC)
  • In the KRAS wild-type subpopulation (n=676), patients received a median of 26 infusions of EU-approved cetuximab (range 1-224)
  • Post hoc analyses of efficacy data were performed on patient subgroups defined by KRAS mutation status

CRYSTAL study: Extended RAS post hoc analysis

In another post hoc analysis of the CRYSTAL study, patient tumor samples with predefined RAS mutations other than KRAS exon 2 were evaluated. In addition, treatment effect in patients with any evaluable RAS wild-type tumor sample was also evaluated.3

RAS subpopulation of the KRAS wild-type subgroup

CRYSTAL study design diagram of RAS wild-type mCRC post hoc analysis

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  • Among patients with KRAS exon 2 wild-type tumors (n=666)†, 65% (n=430) were evaluable for RAS mutation status. Of those, 85% (n=367) had RAS wild-type tumors

*Patients treated with EU-approved cetuximab + FOLFIRI received an initial IV infusion of EU-approved cetuximab 400 mg/m2 and weekly infusions of 250 mg/m2 administered 1 hour prior to chemotherapy. For all patients, the FOLFIRI regimen included 14-day cycles of irinotecan (180 mg/m2 IV on day 1), folinic acid (400 mg/m2 [racemic] or 200 mg/m2 [L-form] IV on day 1), and 5-fluorouracil (400 mg/m2 bolus on day 1 followed by 2400 mg/m2 as a 46-hour continuous infusion).1

†676 patients with KRAS wild-type tumors were enrolled. Of those, 666 received study treatment.

IV=intravenous.

CRYSTAL study safety profile1

No new relevant safety findings were identified in the RAS subpopulation analysis3

CRYSTAL study and post hoc analyses: Table of most common adverse reactions

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  • The CRYSTAL study used EU-approved cetuximab. US-licensed ERBITUX® (cetuximab) provides approximately 22% higher exposure to cetuximab relative to the EU-approved cetuximab. The data provided for the CRYSTAL study are consistent in incidence and severity of adverse reactions with those seen for ERBITUX in this indication. The tolerability of the recommended dose is supported by the safety data from additional studies of ERBITUX

*Adverse reactions occurring in at least 10% of ERBITUX combination arm with a frequency of at least 5% greater than that seen in the FOLFIRI arm.

†Adverse reactions were graded using the NCI CTC, V 2.0.

‡Infusion-related reaction is defined as any event meeting the medical concepts of allergy/anaphylaxis at any time during the clinical study or any event occurring on the first day of dosing and meeting the medical concepts of dyspnea and fever or by the following events using MedDRA preferred terms: “acute myocardial infarction,” “angina pectoris,” “angioedema,” “autonomic seizure,” “blood pressure abnormal,” “blood pressure decreased,” “blood pressure increased,” “cardiac failure,” “cardiopulmonary failure,” “cardiovascular insufficiency,” “clonus,” “convulsion,” “coronary no-reflow phenomenon,” “epilepsy,” “hypertension,” “hypertensive crisis,” “hypertensive emergency,” “hypotension,” “infusion-related reaction,” “loss of consciousness,” “myocardial infarction,” “myocardial ischaemia,” “prinzmetal angina,” “shock,” “sudden death,” “syncope,” or “systolic hypertension.”

MedDRA=Medical Dictionary for Regulatory Activities; NCI CTC=National Cancer Institute Common Toxicity Criteria.

Estimated distribution of RAS mutations* in mCRC5

  • KRAS and NRAS are closely related members of the RAS oncogene family6
  • Previously, 58% of patients were thought to have KRAS wild-type exon 2
  • It is now known there are other RAS mutations that had not been identified
  • An estimated 53% of mCRC tumors harbor RAS mutations*
Pie chart showing the estimated distribution of RAS mutations in mCRC

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*RAS mutations are defined as somatic mutations in exon 2 (codons 12 and 13), exon 3 (codons 59 and 61), and exon 4 (codons 117 and 146) of either KRAS or NRAS.

†Other RAS mutations defined as KRAS exon 2 wild-type mCRC that harbors mutations in KRAS exon 3 or 4 or NRAS exons 2-4.

National Comprehensive Cancer Network® (NCCN®) recommends RAS testing at mCRC diagnosis7,8

NCCN recommendation for RAS testing at diagnosis of mCRC

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ERBITUX (cetuximab) FDA-approved Indication1

ERBITUX is indicated for the treatment of KRAS wild-type, epidermal growth factor receptor (EGFR)-expressing metastatic colorectal cancer (mCRC) as determined by FDA-approved tests for this use in combination with FOLFIRI (irinotecan, 5-fluorouracil, leucovorin) for first-line treatment.

Limitation of Use: ERBITUX is not indicated for treatment of RAS-mutant colorectal cancer or when the results of the RAS mutation tests are unknown.

*NCCN recommends that all patients with metastatic colorectal cancer should have tumor tissue genotyped for RAS (KRAS exon 2 or non-exon 2 and NRAS) and BRAF mutations. Microsatellite instability (MSI) or mismatch repair (MMR) testing should also be performed for all patients with metastatic disease.

REFERENCES

  1. ERBITUX (cetuximab) [package insert]. Indianapolis, IN: Eli Lilly and Company, its subsidiaries or affiliates.
  2. Van Cutsem E, et al. J Clin Oncol. 2011;29(15):2011-2019.
  3. Van Cutsem E, et al. J Clin Oncol. 2015;33(7):692-700.
  4. Miller AB, et al. Cancer. 1981;47(1):207-214.
  5. Sorich MJ, et al. Ann Oncol. 2015;26(1):13-21.
  6. Custodio A, Feliu J. Crit Rev Oncol Hematol. 2013;85(1):45-81.
  7. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Colon Cancer V.2.2017. © National Comprehensive Cancer Network, Inc 2017. All rights reserved. Accessed April 10, 2017. To view the most recent and complete version of the guidelines, go online to NCCN.org. NCCN makes no warranties of any kind whatsoever regarding their content, use, or application and disclaims any responsibility for their application or use in any way.
  8. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Rectal Cancer V.3.2017. © National Comprehensive Cancer Network, Inc 2017. All rights reserved. Accessed April 10, 2017. To view the most recent and complete version of the guidelines, go online to NCCN.org. NCCN makes no warranties of any kind whatsoever regarding their content, use, or application and disclaims any responsibility for their application or use in any way.

INDICATIONS

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)
  • ERBITUX is indicated in combination with platinum-based therapy with 5-FU for the first-line treatment of patients with recurrent locoregional disease or metastatic squamous cell carcinoma of the head and neck
  • ERBITUX, as a single agent, is indicated for the treatment of patients with recurrent or metastatic squamous cell carcinoma of the head and neck for whom prior platinum-based therapy has failed

Metastatic Colorectal Cancer

ERBITUX is indicated for the treatment of KRAS wild-type, epidermal growth factor receptor (EGFR)-expressing, metastatic colorectal cancer (mCRC) as determined by FDA-approved tests for this use:

  • In combination with FOLFIRI (irinotecan, 5-fluorouracil, leucovorin) for first-line treatment
  • In combination with irinotecan in patients who are refractory to irinotecan-based chemotherapy
  • As a single agent in patients who have failed oxaliplatin- and irinotecan-based chemotherapy or who are intolerant to irinotecan

Limitation of Use: ERBITUX is not indicated for treatment of RAS-mutant colorectal cancer or when the results of the RAS mutation tests are unknown.

INDICATIONS

Head and Neck Cancer

  • ERBITUX® (cetuximab), in combination with radiation therapy, is approved for the initial treatment of a certain type of locally or regionally advanced head and neck cancer
  • ERBITUX, in combination with platinum-based chemotherapy with 5-fluorouracil, is approved for the initial treatment of patients with a certain type of head and neck cancer whose tumor has returned in the same location or spread to other parts of the body
  • ERBITUX is also approved for use alone to treat patients with a certain type of head and neck cancer whose tumor has returned in the same location or spread to other parts of the body and whose disease has progressed following platinum-based chemotherapy

Metastatic Colorectal Cancer

ERBITUX is approved for the treatment of certain patients who have colorectal cancer that has spread to other parts of the body. Only patients whose tumors are KRAS wild-type (which means they have a KRAS mutation-negative gene), and whose tumors have a protein called epidermal growth factor receptor (EGFR), should receive ERBITUX. FDA-approved tests are used to determine if tumors have these particular traits. Treatment with ERBITUX is given in the following three ways:

  • In combination with FOLFIRI (irinotecan, 5-fluorouracil, leucovorin) for patients who are being treated for this type of cancer for the first time
  • In combination with another chemotherapy drug, irinotecan, for patients whose disease has progressed after receiving chemotherapy with irinotecan
  • As a single agent:
    • For patients whose disease has progressed after receiving both irinotecan and oxaliplatin
    • For patients who are unable to tolerate chemotherapy with irinotecan

ERBITUX is not approved to treat colorectal cancer in patients whose tumors have mutations in genes called RAS (often called "RAS mutant"), or in patients for whom the mutational status of the genes is not known.

ERBITUX is available by prescription only.

IMPORTANT SAFETY INFORMATION INCLUDING BOXED WARNINGS

WARNING: SERIOUS INFUSION REACTIONS and CARDIOPULMONARY ARREST

Infusion Reactions:

Serious infusion reactions occurred with the administration of ERBITUX® (cetuximab) 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.

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

WARNING: ALLERGIC REACTIONS and HEART ATTACK

Allergic Reactions:

  • Severe allergic reactions due to ERBITUX® (cetuximab) therapy have occurred in 42 of 1373 patients (3%) receiving ERBITUX during clinical studies, resulting in death in less than 1 in 1000 patients
    • Symptoms can include trouble with breathing (including tightening of the airways, wheezing, or hoarseness), low blood pressure, shock, loss of consciousness, and/or heart attack. Report these signs and symptoms of infusion reactions, as well as fever, chills, or breathing problems to your doctor or nurse
    • Approximately 90% of the severe allergic reactions occurred with the first dose of ERBITUX, although some patients experienced their first severe allergic reaction during a subsequent dose of ERBITUX
    • Your doctor or nurse should watch you closely for these symptoms during treatment and may need to stop therapy in the event of an allergic reaction
    • Severe allergic reactions require that treatment with ERBITUX be stopped immediately and not started again

Heart Attack:

  • Heart attack and/or sudden death occurred in 4 of 208 patients (2%) with head and neck cancer treated with radiation therapy and ERBITUX, as compared to none of 212 patients treated with radiation therapy alone
  • Heart problems resulting in death and/or sudden death occurred in 7 of 219 patients (3%) with head and neck cancer treated with platinum-based chemotherapy with 5-fluorouracil and cetuximab compared to 4 of 215 patients (2%) treated with chemotherapy alone, based on a study conducted in Europe using European cetuximab
  • Notify your doctor if you have a history of any heart disease

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

Increased Tumor Progression, Increased Mortality, or Lack of Benefit in Patients with RAS-Mutant mCRC

  • ERBITUX is not indicated for the treatment of patients with colorectal cancer that harbor somatic mutations in exon 2 (codons 12 and 13), exon 3 (codons 59 and 61), and exon 4 (codons 117 and 146) of either KRAS or NRAS
  • Based on retrospective subset analyses of RAS-mutant and wild-type populations across several randomized clinical trials of anti-EGFR-directed monoclonal antibodies, including Study 4, use of cetuximab in patients with RAS mutations resulted in no clinical benefit with treatment related toxicity

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
  • The most frequent adverse reactions seen in patients with KRAS wild-type, EGFR-expressing metastatic colorectal cancer treated with EU-approved cetuximab + FOLFIRI (n=317) versus FOLFIRI alone (n=350) (incidence ≥50%) were acne-like rash (86% vs 13%) and diarrhea (66% vs 60%). The most common grade 3/4 adverse reactions (≥10%) included: neutropenia (31% vs 24%), acne-like rash (18% vs <1%), and diarrhea (16% vs 10%). U.S.-licensed ERBITUX provides approximately 22% higher exposure to cetuximab relative to the EU-approved cetuximab. The data provided above are consistent in incidence and severity of adverse reactions with those seen for ERBITUX in this indication. The tolerability of the recommended dose is supported by safety data from additional studies of ERBITUX
  • The most frequent adverse reactions seen in patients with KRAS wild-type, EGFR-expressing metastatic colorectal cancer treated with ERBITUX + best supportive care (BSC) (n=118) versus BSC alone (n=124) (incidence ≥50%) were rash/desquamation (95% vs 21%), fatigue (91% vs 79%), nausea (64% vs 50%), dry skin (57% vs 15%), pain-other (59% vs 37%), and constipation (53% vs 38%). The most common grade 3/4 adverse reactions (≥10%) included: fatigue (31% vs 29%), pain-other (18% vs 10%), rash/desquamation (16% vs 1%), dyspnea (16% vs 13%), other-gastrointestinal (12% vs 5%), and infection without neutropenia (11% vs 5%)
  • The most frequent adverse reactions seen in patients with EGFR-expressing metastatic colorectal cancer (n=354) treated with ERBITUX plus irinotecan in clinical trials (incidence ≥50%) were acneiform rash (88%), asthenia/malaise (73%), diarrhea (72%), and nausea (55%). The most common grade 3/4 adverse reactions (≥10%) included: diarrhea (22%), leukopenia (17%), asthenia/malaise (16%), and acneiform rash (14%)

Please see full Prescribing Information for ERBITUX, including Boxed Warnings regarding infusion reactions and cardiopulmonary arrest.

CE HCP ISI_ALL 17JUN2015

Lung Disease

  • Lung disease, which resulted in one death, occurred in 4 of 1570 patients (<0.5%) receiving ERBITUX in several clinical trials in colorectal cancer and head and neck cancer
    • Notify your doctor if you develop shortness of breath while receiving ERBITUX
    • ERBITUX treatment should be stopped if symptoms worsen or lung disease is confirmed

Skin Problems

  • In several clinical trials in colorectal cancer and head and neck cancer with ERBITUX, skin problems including an acne-like rash, skin drying and cracking, infections (including infections of the blood, skin, eyes, and lips), and abnormal hair growth were seen
    • Sun exposure may worsen these effects
    • Patients taking ERBITUX should wear sunscreen and hats to limit sun exposure while receiving and for 2 months following the last dose of ERBITUX
    • Severe reactions with symptoms of rash; blistering of the skin, mouth, eyes, and genitals; and shedding of the skin have been seen in patients treated with ERBITUX. These reactions may be life-threatening and possibly lead to death. It is not clear if these reactions are related to the way ERBITUX works or to an immune response, such as Stevens-Johnson syndrome or toxic epidermal necrolysis
    • A related nail disorder that causes painful swelling of the skin around the nails—most often of the large toes and thumbs—also was reported
    • Notify your doctor if you develop any of these symptoms while receiving ERBITUX

ERBITUX Plus Chemotherapy and Radiation

  • In a controlled study, 940 patients with head and neck cancer received either ERBITUX with radiation therapy and cisplatin (a cancer drug) or radiation therapy and cisplatin alone. Adding ERBITUX resulted in an increase in occurrence of severe or life-threatening redness and sores of the lining of the mouth, lips or throat and other digestive organs; skin reactions caused by certain cancer drugs given after radiation; acne-like rash; heart problems and blood electrolyte disturbances compared to radiation and cisplatin alone
  • Side effects resulting in death occurred in 20 patients (4.4%) in the ERBITUX treatment arm, and 14 patients (3.0%) in the radiation therapy and cisplatin alone treatment arm
  • Nine patients in the ERBITUX treatment arm (2.0%) experienced decreased blood flow to the heart compared to 4 patients (0.9%) in the radiation therapy and cisplatin alone treatment arm
  • The main point of the study was to measure how long patients survived before their cancer got worse. Adding ERBITUX to radiation and cisplatin did not improve this measure

Electrolyte Depletion

  • Low levels of magnesium and accompanying low calcium and potassium levels have been reported with ERBITUX when given by itself and in combination with other cancer drugs
    • Your doctor or nurse should periodically monitor your blood electrolyte levels and administer intravenous replacement as needed

Increased Tumor Growth, Increased Death, or Lack of Benefit in Patients with RAS-Mutation Positive or “Mutant” Colorectal Cancer

  • You should not be treated with ERBITUX if you have colorectal cancer that has mutations in the RAS genes because you will not benefit from ERBITUX treatment and will experience side effects

Late Radiation Side Effects

  • The percentage of late radiation side effects was higher in patients given ERBITUX with radiation therapy compared with patients given radiation therapy alone
    • The following sites were affected: organs that produce saliva (65% versus 56%), voice box (52% versus 36%), tissue below the skin (49% versus 45%), lining of the mouth and some organs (48% versus 39%), food pipe (44% versus 35%), and skin (42% versus 33%) in the patients given ERBITUX and radiation versus patients given radiation alone, respectively
  • The percentage of severe late radiation side effects was similar among patients given radiation therapy alone and patients given ERBITUX plus radiation therapy

Pregnancy and Nursing

  • Notify your doctor if you are pregnant or if you become pregnant while receiving ERBITUX. Contraception must be used, in both males and females, during ERBITUX therapy and for 6 months following the last dose of ERBITUX. ERBITUX may be passed from the mother to the developing fetus, and may cause harm to the fetus. ERBITUX should only be used during pregnancy if the potential benefit is greater than the potential risk to the fetus
  • ERBITUX may be passed through human breast milk. Because of the potential for serious side effects in nursing infants from ERBITUX, nursing is not recommended during ERBITUX therapy and for 2 months following the last dose of ERBITUX

Additional Side Effects

In studies of ERBITUX:

  • The most serious side effects associated with ERBITUX are: allergic reactions, heart attack, skin problems, skin irritation in the radiation area, infection, kidney failure, lung disease, and blood clots in the lung
  • The most frequent side effects associated with ERBITUX (reported in at least 25% of patients) are skin problems (including rash, itching, and nail changes), headache, diarrhea, and infection

In a study of ERBITUX and radiation therapy given to 208 patients versus radiation therapy alone given to 212 patients with head and neck cancer:

  • The most frequent side effects were: acne-like rash (87% versus 10%), skin irritation in the radiation area (86% versus 90%), weight loss (84% versus 72%), and feeling weak (56% versus 49%)
  • Serious side effects reported by at least 10% of patients that received ERBITUX in combination with radiation therapy versus radiation therapy alone included: skin irritation in the radiation area (23% versus 18%), acne-like rash (17% versus 1%), and weight loss (11% versus 7%)

In a study of European cetuximab in combination with platinum-based chemotherapy with 5-fluorouracil given to 219 patients versus chemotherapy alone given to 215 patients with head and neck cancer:

  • The most frequent side effects were: acne-like rash (70% versus 2%), nausea (54% versus 47%), and infection (44% versus 27%)
  • Serious side effects reported by at least 10% of patients in either arm were: infection (11% versus 8%)
  • ERBITUX yields approximately 22% higher blood levels of cetuximab relative to European cetuximab. It is possible that U.S. patients receiving ERBITUX may experience more frequent or severe side effects than patients in the study conducted in Europe

In a study of European cetuximab in combination with FOLFIRI (irinotecan, 5-fluorouracil, leucovorin) given to 317 patients versus FOLFIRI alone given to 350 patients with colorectal cancer that had spread to other parts of the body whose tumors were KRAS wild-type and whose tumors had a protein called Epidermal Growth Factor Receptor (EGFR):

  • The most frequent side effects were: acne-like rash (86% versus 13%) and diarrhea (66% versus 60%)
  • Serious side effects reported by at least 10% of patients in either arm were: abnormal decrease in white blood cell count (31% versus 24%), acne-like rash (18% versus <1%), and diarrhea (16% versus 10%)
  • ERBITUX yields approximately 22% higher blood levels of cetuximab relative to European cetuximab. In this study, the side effects and severity of adverse reactions seen with European cetuximab were consistent with other studies of U.S. patients receiving ERBITUX for metastatic colorectal cancer

In a study where ERBITUX and supportive care were given to 118 patients versus supportive care which was given to 124 patients with colorectal cancer that had spread to other parts of the body whose tumors were KRAS wild-type and whose tumors had a protein called Epidermal Growth Factor Receptor (EGFR):

  • The most frequent side effects reported were: rash or shedding of the outer layer of the skin (95% versus 21%), feeling tired (91% versus 79%), nausea (64% versus 50%), dry skin (57% versus 15%), other pain (59% versus 37%), and constipation (53% versus 38%)
  • Serious side effects reported by at least 10% of patients included: fatigue (31% versus 29%), other pain (18% versus 10%), rash or shedding of the outer layer of the skin (16% versus 1%), shortness of breath (16% versus 13%), other intestinal problems (12% versus 5%) and infection without abnormal decrease in white blood cell count (11% versus 5%)

In studies where ERBITUX and irinotecan were given to 354 patients with colorectal cancer that had spread to other parts of the body whose tumors had a protein called Epidermal Growth Factor Receptor (EGFR):

  • The most frequent side effects reported were: acne-like rash (88%), feeling weakness or discomfort (73%), diarrhea (72%), and nausea (55%)
  • Serious side effects reported by at least 10% of patients included: diarrhea (22%), decrease in white blood cell count (17%), feeling weakness or discomfort (16%), and acne-like rash (14%)

You are encouraged to report negative side effects of Prescription drugs to the FDA. Visit www.fda.gov/safety/medwatch or call 1-800-FDA-1088.

Please see full Prescribing Information for ERBITUX, including Boxed Warnings for allergic reactions and heart attack.

CE CON ISI_ALL 17JUN2015

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