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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: SEVERE ALLERGIC REACTIONS AND HEART ATTACK

Severe allergic reactions due to ERBITUX® (cetuximab) therapy occurred in 42 of 1373 patients (3%) receiving ERBITUX during clinical studies; 1 patient died

  • 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, and/or chills to your doctor or nurse
  • Approximately 90% of the severe allergic reactions occurred with the first treatment with ERBITUX (even if the patient had been premedicated with antihistamines), although some patients experienced their first severe allergic reaction during a later treatment
  • Your doctor or nurse should watch you closely for these symptoms during treatment and for 1 hour following treatment and may need to stop therapy in the event of an allergic reaction
  • If you have a severe allergic reaction, treatment with ERBITUX must be stopped immediately and not started again

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 cetuximab and platinum-based chemotherapy with 5-fluorouracil compared to 4 of 215 patients (2%) treated with chemotherapy alone, in 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

IMPORTANT SAFETY INFORMATION FOR ERBITUX® (cetuximab)

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: SEVERE ALLERGIC REACTIONS AND HEART ATTACK

Severe allergic reactions due to ERBITUX® (cetuximab) therapy occurred in 42 of 1373 patients (3%) receiving ERBITUX during clinical studies; 1 patient died

  • 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, and/or chills to your doctor or nurse
  • Approximately 90% of the severe allergic reactions occurred with the first treatment with ERBITUX (even if the patient had been premedicated with antihistamines), although some patients experienced their first severe allergic reaction during a later treatment
  • Your doctor or nurse should watch you closely for these symptoms during treatment and for 1 hour following treatment and may need to stop therapy in the event of an allergic reaction
  • If you have a severe allergic reaction, treatment with ERBITUX must be stopped immediately and not started again

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 cetuximab and platinum-based chemotherapy with 5-fluorouracil compared to 4 of 215 patients (2%) treated with chemotherapy alone, in 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)

Hypomagnesemia and Electrolyte Abnormalities

  • 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 and hereafter referred to as “RAS.”
  • 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

Embryo-Fetal Toxicity

  • Based on animal data and its mechanism of action, ERBITUX can cause fetal harm when administered to a pregnant woman. There are no available data for ERBITUX exposure in pregnant women. In an animal reproduction study, intravenous administration of cetuximab once weekly to pregnant cynomolgus monkeys during the period of organogenesis resulted in an increased incidence of embryolethality and abortion. Disruption or depletion of EGFR in animal models results in impairment of embryo-fetal development including effects on placental, lung, cardiac, skin, and neural development. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with ERBITUX and for 2 months after 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%)

Use in Specific Populations

  • Lactation: There is no information regarding the presence of ERBITUX in human milk, the effects of the breastfed infant, or the effects on milk production. Human IgG antibodies can be excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from ERBITUX, advise women not to breast-feed during treatment with ERBITUX and for at least 2 months following the last dose of ERBITUX.
  • Pediatric Use: The safety and effectiveness of ERBITUX in pediatric patients have not been established. No new safety signals were identified in pediatric patients when ERBITUX in combination with irinotecan was administered in an open-label, single-arm dose-finding study in 27 patients with refractory solid tumors aged 1 to 12 years old.
  • Geriatric Use: In mCRC clinical studies, no overall differences in safety or efficacy of ERBITUX were observed between patients >65 years of age and younger patients. In SCCHN clinical studies of ERBITUX there were insufficient number of patients >65 years of age to determine whether they respond differently from younger patients.

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

CE HCP ISI_ALL 18MAY2018

  • 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 and/or a dry cough while receiving ERBITUX
    • ERBITUX treatment should be stopped if breathing symptoms worsen, and should not be restarted if lung disease is diagnosed
  • 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 in several clinical trials in colorectal cancer and head and neck cancer with ERBITUX.
    • Sun exposure may worsen these effects
    • Patients taking ERBITUX should wear sunscreen and hats to limit sun exposure during treatment and for 2 months after 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
  • Risks when using ERBITUX with radiation and cisplatin. In a study of 940 patients with head and neck cancer, patients received either a combination of radiation and cisplatin (a cancer drug), or ERBITUX in combination with radiation and cisplatin. 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 plus radiation and cisplatin treatment arm, and 14 patients (3.0%) in the radiation therapy and cisplatin alone treatment arm
    • Nine patients in the ERBITUX plus radiation and cisplatin 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
  • 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 during and for at least 8 weeks after treatment with ERIBUTX, and administer intravenous replacement as needed
  • You should not be treated with ERBITUX if you have colorectal cancer with mutations in the RAS genes because you will not benefit from ERBITUX treatment and will experience side effects
  • The occurrence 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 occurrence of severe late radiation side effects was similar among patients given radiation therapy alone and patients given ERBITUX plus radiation therapy
  • ERBITUX can harm your unborn baby. If you are able to become pregnant, you should use effective contraception during treatment with ERBITUX and for 2 months after the last dose of ERBITUX

What are the most common side effects of ERBITUX?

  • The most common side effects (all grades of severity) reported in patients with head and neck cancer treated with ERBITUX in combination with radiation therapy versus radiation therapy alone (incidence ≥25%) were: feeling weak, fever, nausea, vomiting, weight loss, dehydration, elevated liver enzymes in blood tests, sore throat, acne-like rash, and skin irritation. The most common serious side effects (incidence ≥10%) reported by patients included skin irritation in the radiation area, acne-like rash, and weight loss.
  • The most common side effects (all grades of severity) in patients with head and neck cancer treated with the European version of ERBITUX in combination with platinum-based chemotherapy with 5-fluorouracil versus chemotherapy alone (incidence ≥25%) were: acne-like rash, nausea, infection, rash, diarrhea and a psychological disorder characterized by a loss of appetite. Most common serious side effects (incidence ≥10%) reported by patients in either arm was: infection. ERBITUX results in approximately 22% higher blood levels of cetuximab as compared to the European version of ERBITUX. 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.
  • The most common side effects (all grades of severity) in patients with Epidermal Growth Factor Receptor (EGFR) positive, KRAS wild-type colorectal cancer that has spread to other parts of the body who were treated with the European version of ERBITUX in combination with FOLFIRI (irinotecan, 5-fluorouracil, leucovorin) versus FOLFIRI alone (incidence ≥25%) were: abnormal decrease in white blood cell count, diarrhea, sore mouth, fever, a psychological disorder characterized by a loss of appetite and a skin rash which looks like severe acne. Most common serious side effects (incidence ≥10%) reported by patients in either arm were: abnormal decrease in white blood cell count, acne-like rash, and diarrhea. ERBITUX results in approximately 22% higher blood levels of cetuximab as compared to the European version of ERBITUX. In this study, the type and severity of side effects seen with European cetuximab were similar to other studies of U.S. patients receiving ERBITUX for metastatic colorectal cancer
  • The most common side effects (all grades of severity) in patients with Epidermal Growth Factor Receptor (EGFR) positive, KRAS wild-type colorectal cancer that has spread to other parts of the body who were treated with ERBITUX and supportive care versus supportive care alone (incidence ≥25%) were: rash or shedding of the outer layer of the skin, dry skin, itchy skin, other skin problems, nail changes, feeling tired, fever, other pain, headache, shortness of breath, cough, nausea, constipation, diarrhea, vomiting, sore mouth, infection without decrease in white blood cell count, sensory neuropathy (weakness, numbness and pain from nerve damage usually in the hands and feet) and problems sleeping. Most common serious side effects (incidence ≥10%) reported by patients included: fatigue, other pain, rash or shedding of the outer layer of the skin, shortness of breath, other intestinal problems and infection without abnormal decrease in white blood cell count.
  • The most common side effects (all grades of severity) in patients with colorectal cancer that has spread to other parts of the body whose tumors had a protein called Epidermal Growth Factor Receptor (EGFR) treated with ERBITUX and irinotecan were: acne-like rash, feeling weakness or discomfort, diarrhea, and nausea. The most common serious side effects reported included: diarrhea, decrease in white blood cell count, feeling weakness or discomfort, and acne-like rash.

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

What should I tell my doctor before starting treatment with ERBITUX?

Before you start treatment with ERBITUX, tell your doctor:
  • If you have any history of heart disease or a heart condition.
  • If you have a history of breathing problems or other lung problems.
  • If you are pregnant or if you plan on becoming pregnant. Because ERBITUX can harm an unborn baby, you should use contraception and not become pregnant during treatment with ERBITUX and for at least 2 months after your last dose of ERBITUX. If you become pregnant during your treatment or within 2 months after your last dose, discuss this with your doctor.
  • If you are breastfeeding or plan to breastfeed. ERBITUX may be passed through human breast milk. Because of the potential for serious side effects in nursing infants from ERBITUX, you should not breastfeed during ERBITUX therapy and for 2 months after the last dose of ERBITUX.
    • Tell your doctor about all the medications you are taking, including prescription and over-the-counter medications.

ERBITUX is available by prescription only.

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

CE CON ISI_ALL 06JUN2018

PP-CE-US-0499   06/2018 © Lilly USA, LLC 2018. All rights reserved. This site is intended for US healthcare professionals only.

PP-CE-US-0499   06/2018 © Lilly USA, LLC 2018. All rights reserved. This site is intended for US residents ages 18 and over.

ERBITUX® is a registered trademark owned or licensed by Eli Lilly and Company, its subsidiaries, or affiliates. Models used for illustrative purposes only. Not actual patients.