1.1 Squamous Cell Carcinoma of the Head and Neck (SCCHN)

ERBITUX® is indicated:

• in combination with radiation therapy for the initial treatment of locally or regionally advanced squamous cell carcinoma of the head and neck (SCCHN).
• in combination with platinum-based therapy with fluorouracil for the first-line treatment of patients with recurrent locoregional disease or metastatic SCCHN.
• as a single-agent for the treatment of patients with recurrent or metastatic SCCHN for whom prior platinum-based therapy has failed.

1.2 K-Ras Wild-type, EGFR-expressing Colorectal Cancer (CRC)

ERBITUX is indicated for the treatment of K-Ras wild-type, epidermal growth factor receptor (EGFR)-expressing, metastatic colorectal cancer (mCRC) as determined by an FDA-approved test [see Dosage and Administration (2.2)]:

• in combination with FOLFIRI (irinotecan, 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.

Limitations of Use: ERBITUX is not indicated for treatment of Ras-mutant colorectal cancer or when the results of the Ras mutation tests are unknown [see Warnings and Precautions (5.7)].

1.3 BRAF V600E Mutation-Positive Metastatic Colorectal Cancer (CRC)

ERBITUX is indicated, in combination with encorafenib, for the treatment of adult patients with metastatic colorectal cancer (CRC) with a BRAF V600E mutation, as detected by an FDA-approved test, after prior therapy [see Dosage and Administration (2.3)].

2.1 Patient Selection

Select patients with metastatic colorectal cancer (CRC) for treatment with ERBITUX based on the presence of:

• Ras wild-type, EGFR-expressing CRC [see Clinical Studies (14.2)], or
• BRAF V600E mutation-positive metastatic CRC [see Clinical Studies (14.3)]

Information on FDA-approved tests for the detection of K-Ras or BRAF V600E mutations in CRC in patients with metastatic CRC is available at: http://www.fda.gov/CompanionDiagnostics.

2.2 Recommended Dosage for Squamous Cell Carcinoma of the Head and Neck (SCCHN)

2.3 Recommended Dosage for Colorectal Cancer (CRC)

As a single-agent or in combination with irinotecan or FOLFIRI (irinotecan, fluorouracil, leucovorin)

Administer Erbitux as a single-agent or in combination with irinotecan or FOLFIRI (irinotecan, fluorouracil, leucovorin) on a weekly or biweekly schedule.

Weekly Dosage

• Initial dose: 400 mg/m2 administered as a 120-minute intravenous infusion
• Subsequent doses: 250 mg/m2 administered as a 60-minute infusion every week

Biweekly Dosage

• Initial and subsequent doses: 500 mg/m2 administered as a 120-minute intravenous infusion every 2 weeks

Complete ERBITUX administration 1 hour prior to irinotecan or FOLFIRI. Continue treatment until disease progression or unacceptable toxicity.

In combination with encorafenib

• The recommended initial dose is 400 mg/m2 administered as a 120-minute intravenous infusion in combination with encorafenib.
• The recommended subsequent dosage is 250 mg/m2 weekly as a 60-minute infusion in combination with encorafenib until disease progression or unacceptable toxicity.

Refer to the encorafenib prescribing information for recommended encorafenib dosage information.

2.4 Premedication

Premedicate with a histamine-1 (H1) receptor antagonist intravenously 30–60 minutes prior to the first dose or subsequent doses as deemed necessary [see Warnings and Precautions (5.1)].

2.5 Dosage Modifications for Adverse Reactions

Reduce, delay, or discontinue ERBITUX to manage adverse reactions as described in Table 1.

2.6 Preparation for Administration

• The solution should be clear and colorless and may contain a small amount of easily visible, white, amorphous, cetuximab particulates. Do not shake or dilute.
• Visually inspect for foreign particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use if solution is discolored, cloudy, or contains foreign particulate matter.
• Do not administer ERBITUX as an intravenous push or bolus.
• Administer via infusion pump or syringe pump. Do not exceed an infusion rate of 10 mg/min.
• Administer through a low protein binding 0.22-micrometer in-line filter.

5.1 Infusion Reactions

ERBITUX can cause serious and fatal infusion reactions. Infusion reactions of any grade occurred in 8.4% of 1373 patients who received ERBITUX across clinical trials. Severe (Grades 3 and 4) infusion reactions occurred in 2.2% of patients [see Adverse Reactions (6.1)]. Signs and symptoms included rapid onset of airway obstruction (bronchospasm, stridor, hoarseness), hypotension, shock, loss of consciousness, myocardial infarction, and/or cardiac arrest.

The risk of anaphylactic reactions may be increased in patients with a history of tick bites, red meat allergy, or in the presence of IgE antibodies directed against galactose-α-1,3-galactose (alpha-gal). Consider testing patients for alpha-gal IgE antibodies using FDA-cleared methods prior to initiating ERBITUX. Negative results for alpha-gal antibodies do not rule out the risk of severe infusion reactions.

Approximately 90% of severe infusion reactions occurred with the first infusion despite premedication with antihistamines. Infusion reactions may occur during or several hours following completion of the infusion.

Premedicate with a histamine-1(H1) receptor antagonist as recommended [see Dosage and Administration (2.4)]. Monitor patients for at least 1 hour following each ERBITUX infusion, in a setting with resuscitation equipment and other agents necessary to treat anaphylaxis. In patients requiring treatment for infusion reactions, monitor for more than 1 hour to confirm resolution of the reaction. Interrupt the infusion and upon recovery, resume the infusion at a slower rate or permanently discontinue ERBITUX based on severity [see Dosage and Administration (2.5)].

5.2 Cardiopulmonary Arrest

ERBITUX can cause cardiopulmonary arrest. Cardiopulmonary arrest or sudden death occurred in 2% of 208 patients treated with radiation therapy and ERBITUX in BONNER. Three patients with prior history of coronary artery disease died at home, with myocardial infarction as the presumed cause of death. One of these patients had arrhythmia and one had congestive heart failure. 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.

In EXTREME, fatal cardiac disorders and/or sudden death occurred in 3% of 219 patients treated with a cetuximab product in combination with platinum-based therapy and fluorouracil.

Carefully consider use of ERBITUX with radiation therapy or platinum-based therapy with fluorouracil in patients with SCCHN with a history of coronary artery disease, congestive heart failure, or arrhythmias. Monitor serum electrolytes, including serum magnesium, potassium, and calcium, during and after ERBITUX [see Warnings and Precautions (5.6)].

5.3 Pulmonary Toxicity

ERBITUX can cause interstitial lung disease (ILD). ILD, including 1 fatality, occurred in <0.5% of 1570 patients receiving ERBITUX in clinical trials.

Monitor patients for signs and symptoms of pulmonary toxicity. Interrupt or permanently discontinue ERBITUX for acute onset or worsening of pulmonary symptoms. Permanently discontinue ERBITUX for confirmed ILD [see Dosage and Administration (2.5)].

5.4 Dermatologic Toxicity

ERBITUX can cause dermatologic toxicities, including acneiform rash, skin drying and fissuring, paronychial inflammation, infectious sequelae (for example, S. aureus sepsis, abscess formation, cellulitis, blepharitis, conjunctivitis, keratitis/ulcerative keratitis with decreased visual acuity, cheilitis), and hypertrichosis.

Acneiform rash occurred in 82% of the 1373 patients who received ERBITUX across clinical trials. Severe (Grades 3 or 4) acneiform rash occurred in 10% of patients [see Adverse Reactions (6.1)]. Acneiform rash usually developed within the first two weeks of therapy; the rash lasted more than 28 days after stopping ERBITUX in most patients.

Life-threatening and fatal bullous mucocutaneous disease with blisters, erosions, and skin sloughing, has been observed in patients who received ERBITUX. It could not be determined whether these mucocutaneous adverse reactions were directly related to EGFR inhibition or to idiosyncratic immune-related effects (e.g., Stevens-Johnson syndrome or toxic epidermal necrolysis).

Monitor patients receiving ERBITUX for dermatologic toxicities and infectious sequelae. Instruct patients to limit sun exposure during ERBITUX therapy. Withhold, reduce dose or permanently discontinue ERBITUX based on severity of acneiform rash or mucocutaneous disease [see Dosage and Administration (2.5)].

5.5 Risks Associated with Use in Combination with Radiation 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 and 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 4% of patients in the ERBITUX combination arm and 3% in the control arm. In the ERBITUX arm, 2% experienced myocardial ischemia compared to 0.9% in the control arm. The main efficacy outcome of the study was progression-free survival (PFS). The addition of ERBITUX to radiation and cisplatin did not improve PFS. ERBITUX is not indicated for the treatment of SCCHN in combination with radiation and cisplatin.

5.6 Hypomagnesemia and Accompanying Electrolyte Abnormalities

ERBITUX can cause hypomagnesemia. Hypomagnesemia occurred in 55% of 365 patients receiving ERBITUX in Study CA225-025 and two other clinical trials in patients with colorectal cancer (CRC) or head and neck cancer, including Grades 3 and 4 in 6% to 17%.

In EXTREME, where a cetuximab product was administered in combination with platinum-based therapy, the addition of cetuximab to cisplatin and fluorouracil resulted in an increased incidence of hypomagnesemia of any grade (14%) and of Grade 3 or 4 hypomagnesemia (7%). Hypomagnesemia of any grade occurred in 4% of patients who received cetuximab, carboplatin, and fluorouracil. No patient experienced Grade 3 or 4 hypomagnesemia [see Adverse Reactions (6.1)].

Hypomagnesemia and accompanying electrolyte abnormalities can occur days to months after initiating ERBITUX. Monitor patients weekly during treatment for hypomagnesemia, hypocalcemia, and hypokalemia, and for at least 8 weeks following the completion of ERBITUX. Replete electrolytes as necessary.

5.7 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 CRC 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 K-Ras or N-Ras and hereafter is referred to as “Ras” or when the Ras status is unknown.

Retrospective subset analyses of Ras-mutant and wild-type populations across several randomized clinical trials, including CRYSTAL, were conducted to investigate the role of Ras mutations on the clinical effects of anti-EGFR-directed monoclonal antibodies. Use of cetuximab in patients with Ras mutations resulted in no clinical benefit with treatment related toxicity. Confirm Ras mutation status in tumor specimens prior to initiating ERBITUX [see Indications and Usage (1.2)].

5.8 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 [see Use in Specific Populations (8.1, 8.3)].

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The data described in Warnings and Precautions reflect exposure to ERBITUX in 1373 patients with SCCHN or CRC enrolled in clinical trials and treated at the recommended dosage for a median of 7 to 14 weeks [see Clinical Studies (14.1, 14.2)]. The most common adverse reactions in clinical trials with ERBITUX as a single-agent or in combination with radiotherapy or chemotherapy [FOLFIRI, irinotecan and 5-fluorouracil/platinum] (incidence ≥25%) include cutaneous adverse reactions (including rash, pruritus, and nail changes), headache, diarrhea, and infection.

6.2 Immunogenicity

As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to cetuximab in the studies below with the incidence of antibodies to cetuximab in other studies or to other products may be misleading.

An ELISA methodology was used to characterize the incidence of anti-cetuximab antibodies. The incidence of anti-cetuximab binding antibodies in 105 patients (from studies I4E-MC-JXBA, I4E-MC-JXBB, and I4E-MC-JXBD) with at least one post-baseline blood sample (≥4 weeks post first ERBITUX administration) was <5%.

6.3 Postmarketing Experience

The following adverse reactions have been identified during post approval use of ERBITUX. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

• Neurologic: Aseptic meningitis
• Gastrointestinal: Mucosal inflammation
• Dermatologic: Stevens-Johnson syndrome, toxic epidermal necrolysis, life-threatening and fatal bullous mucocutaneous disease

8.1 Pregnancy

8.2 Lactation

8.3 Females and Males of Reproductive Potential

8.4 Pediatric Use

The safety and effectiveness of ERBITUX in pediatric patients have not been established. The pharmacokinetics of cetuximab, in combination with irinotecan, were evaluated in pediatric patients with refractory solid tumors in an open-label, single-arm, dose-finding study. ERBITUX was administered once-weekly, at doses up to 250 mg/m2, to 27 patients ranging from 1 to 12 years old; and in 19 patients ranging from 13 to 18 years old. No new safety signals were identified in pediatric patients. The pharmacokinetics of cetuximab between the two age groups were similar following a single dose of 75 mg/m2 and 150 mg/m2. The volume of the distribution appears to be independent of dose and approximates the vascular space of 2 L/m2 to 3 L/m2. Following a single dose of 250 mg/m2, the mean AUC0-inf (CV%) was 17.7 mg*h/mL (34%) in the younger age group (1–12 years, n=9) and 13.4 mg*h/mL (38%) in the adolescent group (13–18 years, n=6). The mean half-life of cetuximab was 110 hours (69 to 188 hours) in the younger group and 82 hours (55 to 117 hours) in the adolescent group.

8.5 Geriatric Use

Of the 1662 patients with advanced colorectal cancer who received ERBITUX with irinotecan, with FOLFIRI or as single-agent in six studies (BOND, IMCL-CP02-9923, IMCL-CP02-0141, IMCL-CP02-0144, CA225-025 and CRYSTAL), 35% of patients were 65 years of age or older. No overall differences in safety or efficacy were observed between these patients and younger patients.

Clinical studies of ERBITUX conducted in patients with head and neck cancer did not include sufficient number of subjects aged 65 and over to determine whether they respond differently from younger subjects.

Of the 216 patients with BRAF V600E mutation positive metastatic CRC who received ERBITUX in combination with encorafenib 300 mg, once daily, 29% were 65 years of age to up to 75 years of age, while 20 (9%) were 75 years of age and over [see Clinical Studies (14.3)].

No overall differences in the safety or effectiveness of ERBITUX plus encorafenib were observed in elderly patients as compared to younger patients.

12.1 Mechanism of Action

The epidermal growth factor receptor (EGFR, HER1, c-ErbB-1) is a transmembrane glycoprotein that is a member of a subfamily of type I receptor tyrosine kinases including EGFR, HER2, HER3, and HER4. The EGFR is constitutively expressed in many normal epithelial tissues, including the skin and hair follicle. Expression of EGFR is also detected in many human cancers including those of the head and neck, colon, and rectum.

Cetuximab binds specifically to the EGFR on both normal and tumor cells, and competitively inhibits the binding of epidermal growth factor (EGF) and other ligands, such as transforming growth factor-alpha. In vitro assays and in vivo animal studies have shown that binding of cetuximab to the EGFR blocks phosphorylation and activation of receptor-associated kinases, resulting in inhibition of cell growth, induction of apoptosis, and decreased matrix metalloproteinase and vascular endothelial growth factor production. Signal transduction through the EGFR results in activation of wild-type Ras proteins, but in cells with activating Ras somatic mutations, the resulting mutant Ras proteins are continuously active regardless of EGFR regulation.

In vitro, cetuximab can mediate antibody-dependent cellular cytotoxicity (ADCC) against certain human tumor types. In vitro assays and in vivo animal studies have shown that cetuximab inhibits the growth and survival of tumor cells that express the EGFR. No anti-tumor effects of cetuximab were observed in human tumor xenografts lacking EGFR expression. The addition of cetuximab to radiation therapy or irinotecan in human tumor xenograft models in mice resulted in an increase in anti-tumor effects compared to radiation therapy or chemotherapy alone.

In the setting of BRAF-mutant CRC, induction of EGFR-mediated MAPK pathway activation has been identified as a mechanism of resistance to BRAF inhibitors. Combinations of a BRAF inhibitor and agents targeting EGFR have been shown to overcome this resistance mechanism in nonclinical models. Coadministration of cetuximab and encorafenib had an anti-tumor effect greater than either drug alone, in a mouse model of colorectal cancer with mutated BRAF V600E.

12.3 Pharmacokinetics

ERBITUX administered as a single-agent or in combination with concomitant chemotherapy or radiation therapy exhibits nonlinear pharmacokinetics. The area under the concentration time curve (AUC) increased in a greater than dose proportional manner while clearance of cetuximab decreased from 0.08 L/h/m2 to 0.02 L/h/m2 as the dose increased from 20 mg/m2 to 200 mg/m2 and plateaued at doses >200 mg/m2.

The systemic exposure of cetuximab after ERBITUX administration was 22% (90% CI: 6%, 38%) higher than that of another cetuximab product used in EXTREME and CRYSTAL.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term animal studies have not been performed to test cetuximab for carcinogenic potential, and no mutagenic or clastogenic potential of cetuximab was observed in the Salmonella-Escherichia coli (Ames) assay or in the in vivo rat micronucleus test. Menstrual cyclicity was impaired in female cynomolgus monkeys receiving weekly doses of 0.4 to 4 times the recommended dose of ERBITUX (based on total body surface area). Cetuximab-treated animals exhibited increased incidences of irregular or absent cycles, as compared to control animals. These effects were initially noted beginning on week 25 and continued through the 6-week recovery period. No effects of cetuximab were observed on measured male fertility parameters (i.e., serum testosterone levels and analysis of sperm counts, viability, and motility) as compared to control male monkeys.

14.1 Squamous Cell Carcinoma of the Head and Neck (SCCHN)

In Combination with Platinum-based Therapy with Fluorouracil

EXTREME (NCT00122460) was an open-label, randomized, multicenter, controlled trial of 442 patients with recurrent locoregional disease or metastatic SCCHN. Patients with no prior therapy for recurrent locoregional disease or metastatic SCCHN were randomized (1:1) to receive a cetuximab product in combination with platinum-based therapy and fluorouracil or platinum-based therapy and fluorouracil alone. Choice of cisplatin or carboplatin was at the discretion of the investigator. Stratification factors were Karnofsky performance status (<80 versus ≥80) and previous chemotherapy. Cisplatin (100 mg/m2 intravenously on Day 1) or carboplatin (AUC 5 mg/mL*min intravenously on Day 1) and fluorouracil (1000 mg/m2/day intravenously on Days 1–4) were administered every 3 weeks (1 cycle) for a maximum of 6 cycles in the absence of disease progression or unacceptable toxicity. Cetuximab was administered intravenously at a 400 mg/m2 initial dose, followed by a 250 mg/m2 weekly dose. In the absence of disease progression or unacceptable toxicity after completion of 6 planned courses of platinum-based therapy, weekly cetuximab as a single-agent could be continued until disease progression or unacceptable toxicity. If chemotherapy was delayed because of adverse reactions, weekly cetuximab was continued. If chemotherapy was discontinued for adverse reactions, weekly cetuximab as a single-agent could be continued until disease progression or unacceptable toxicity. The main efficacy outcome measure was OS. Other outcome measures were PFS and objective response rate (ORR).

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

Efficacy results are presented in Table 9 and Figure 1.

Table 9: Efficacy Results in Recurrent Locoregional Disease or Metastatic SCCHN in EXTREME

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

Figure 1: Kaplan-Meier Curves for Overall Survival in Patients with Recurrent Locoregional Disease or Metastatic SCCHN in EXTREME

CT = Platinum-based therapy with fluorouracil

CET = another cetuximab product

In exploratory subgroup analyses by initial platinum therapy (cisplatin or carboplatin), for patients (N=284) receiving cetuximab in combination with cisplatin and fluorouracil compared to cisplatin and fluorouracil alone, the difference in median OS was 3.3 months (10.6 versus 7.3 months; HR 0.71; 95% CI 0.54, 0.93). The difference in median PFS was 2.1 months (5.6 versus 3.5 months; HR 0.55; 95% CI 0.41, 0.73). The ORR was 39% and 23%, respectively (OR 2.18; 95% CI 1.29, 3.69).

For patients (N=149) receiving cetuximab in combination with carboplatin and fluorouracil compared to carboplatin and fluorouracil alone, the difference in median OS was 1.4 months (9.7 versus 8.3 months; HR 0.99; 95% CI 0.69, 1.43). The difference in median PFS was 1.7 months (4.8 versus 3.1 months, respectively; HR 0.61; 95% CI 0.42, 0.89). The ORR was 30% and 15%, respectively (OR 2.45; 95% CI 1.10, 5.46).

14.2 K-Ras Wild-type, EGFR-expressing, Metastatic Colorectal Cancer (CRC)

In Combination with FOLFIRI

CRYSTAL (NCT00154102) was a randomized, open-label, multicenter, study of 1217 patients with EGFR-expressing, mCRC. Patients were randomized (1:1) to receive either a cetuximab product in combination with FOLFIRI or FOLFIRI alone as first-line treatment. Stratification factors were Eastern Cooperative Oncology Group (ECOG) performance status (0 and 1 versus 2) and region (Western Europe versus Eastern Europe versus other).

FOLFIRI regimen included 14-day cycles of irinotecan (180 mg/m2 intravenously on Day 1), folinic acid (400 mg/m2 [racemic] or 200 mg/m2 [L-form] intravenously on Day 1), and fluorouracil (400 mg/m2 bolus on Day 1 followed by 2400 mg/m2 as a 46-hour continuous infusion). Cetuximab was administered intravenously as a 400 mg/m2 initial dose , followed by 250 mg/m2 weekly administered 1 hour prior to chemotherapy. Study treatment continued until disease progression or unacceptable toxicity. The main efficacy outcome measure was PFS assessed by an independent review committee (IRC). Other outcome measures were OS and ORR.

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

K-Ras mutation status was available for 89% of the patients: 63% had K-Ras wild-type tumors and 37% had K-Ras mutant tumors where testing assessed for the following somatic mutations in codons 12 and 13 (exon 2): G12A, G12D, G12R, G12C, G12S, G12V, G13D. Baseline characteristics and demographics in the K-Ras wild-type subset were similar to that seen in the overall population.

A statistically significant improvement in PFS was observed for the cetuximab with FOLFIRI arm compared with the FOLFIRI arm (median PFS 8.9 vs. 8.1 months, HR 0.85 [95% CI 0.74, 0.99], p-value=0.036). OS was not significantly different at the planned, final analysis based on 838 events (HR=0.93, 95% CI [0.8, 1.1], p-value 0.327).

Results of the planned PFS and ORR analysis in all randomized patients and post-hoc PFS and ORR analysis in subgroups of patients defined by K-Ras mutation status, and post-hoc analysis of updated OS based on additional follow-up (1000 events) in all randomized patients and in subgroups of patients defined by K-Ras mutation status are presented in Table 10 and Figure 2. The treatment effect in the all-randomized population for PFS was driven by treatment effects limited to patients who have K-Ras wild-type tumors. There is no evidence of effectiveness in the subgroup of patients with K-Ras mutant tumors.

Figure 2: Kaplan-Meier Curves for Overall Survival in the K-Ras Wild-type Population in CRYSTAL

As Single-Agent

Study CA225-025 (NCT00079066) was a multicenter, open-label, randomized, clinical trial conducted in 572 patients with EGFR-expressing, previously treated, recurrent mCRC. Patients were randomized (1:1) to receive either ERBITUX with best supportive care (BSC) or BSC alone. ERBITUX was administered intravenously as a 400 mg/m2 initial dose, followed by 250 mg/m2 weekly until disease progression or unacceptable toxicity. The main efficacy outcome measure was OS.

Of the 572 randomized patients, the median age was 63 years, 64% were male, 89% were White, and 77% had baseline ECOG performance status of 0–1. Demographics and baseline characteristics were similar between study arms. All patients were to have received and progressed on prior therapy including an irinotecan-containing regimen and an oxaliplatin-containing regimen.

K-Ras status was available for 79% of the patients: 54% had K-Ras wild-type tumors and 46% had K-Ras mutant tumors where testing assessed for the following somatic mutations in codons 12 and 13 (exon 2): G12A, G12D, G12R, G12C, G12S, G12V, G13D.

Efficacy results are presented in Table 11 and Figure 3.

Table 11: Overall Survival in Previously Treated EGFR-expressing, Metastatic Colorectal Cancer in Study CA225-025 (All Randomized and K-Ras Status)

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

Figure 3: Kaplan-Meier Curves for Overall Survival in Patients with K-Ras Wild-type Metastatic Colorectal Cancer in Study CA225-025

14.3 BRAF V600E Mutation-Positive Metastatic Colorectal Cancer (CRC)

ERBITUX in combination with encorafenib was evaluated in a randomized, active-controlled, open label, multicenter trial (BEACON CRC; NCT02928224). Eligible patients were required to have BRAF V600E mutation-positive metastatic CRC, as detected using the Qiagen therascreen BRAF V600E RGQ polymerase chain reaction (PCR) Kit, with disease progression after 1 or 2 prior regimens. Other key eligibility criteria included absence of prior treatment with a RAF, MEK, or EGFR inhibitor, eligibility to receive cetuximab per local labeling with respect to tumor RAS status, and ECOG performance status (PS) 0–1. Randomization was stratified by ECOG performance status (0 versus 1), prior use of irinotecan (yes versus no), and cetuximab product used (US-licensed versus EU-approved).

Patients were randomized 1:1:1 to one of the following treatment arms:

• ERBITUX in combination with encorafenib 300 mg orally once daily (ERBITUX/encorafenib arm)
• ERBITUX in combination with binimetinib and encorafenib 300 mg orally once daily
• ERBITUX with irinotecan or ERBITUX with FOLFIRI (control arm)

The dosage of cetuximab in all patients was 400 mg/m2 intravenously for the first dose followed by 250 mg/m2 weekly.

Patients in the control arm received ERBITUX with either irinotecan 180 mg/m2 intravenously on Days 1 and 15 of each 28-day cycle or FOLFIRI intravenously (irinotecan 180 mg/m2 on Days 1 and 15; folinic acid 400 mg/m2 on Days 1 and 15; then fluorouracil 400 mg/m2 bolus on Days 1 and 15 followed by fluorouracil 2400 mg/m2 /day by continuous infusion over 2 days).

Treatment continued until disease progression or unacceptable toxicity. Only the results of the approved regimen (ERBITUX in combination with encorafenib) are described below.

The major efficacy outcome measure was OS. Additional efficacy outcome measures included PFS, ORR, and DoR as assessed by blinded independent central review (BICR). OS and PFS were assessed in all randomized patients. ORR and DoR were assessed in the subset of the first 220 patients included in the randomized portion of the ERBITUX/encorafenib and control arm of the study.

A total of 220 patients were randomized to the ERBITUX/encorafenib arm and 221 to the control arm. Of these 441 patients, the median age was 61 years; 53% were female; 80% were White and 15% were Asian. Fifty percent (50%) had baseline ECOG performance status of 0; 66% received 1 prior therapy and 34% received 2; 93% received prior oxaliplatin and 52% received prior irinotecan.

ERBITUX in combination with encorafenib demonstrated a statistically significant improvement in OS, ORR, and PFS compared to the active comparator. Efficacy results are summarized in Table 12 and Figure 4.

Figure 4: Kaplan-Meier Curves for Overall Survival in Patients with BRAF V600E Mutation-Positive Metastatic Colorectal Cancer in BEACON

How Supplied

ERBITUX® (cetuximab) injection is a sterile, preservative-free, clear, colorless solution in a 2 mg/mL single-dose vial supplied as follows:

• 100 mg/50 mL individually packaged in a carton (NDC 66733-948-23)
• 200 mg/100 mL individually packaged in a carton (NDC 66733-958-23)

Storage and Handling

• Store vials under refrigeration at 2° C to 8° C (36° F to 46° F).
• Do not freeze or shake.
• Increased particulate formation may occur at temperatures at or below 0° C (32° F).
• Discard any remaining solution in the infusion container after 8 hours at controlled room temperature or after 12 hours at 2° C to 8° C.
• Discard any unused portion of the vial.

Infusion Reactions

Advise patients that the risk of serious infusion reactions may be increased in patients who have had a tick bite or red meat allergy. Advise patients to contact their healthcare provider and to report signs and symptoms of infusion reactions, including late onset infusion reactions, such as fever, chills, or breathing problems [see Warnings and Precautions (5.1)].

Cardiopulmonary Arrest

Advise patients of the risk of cardiopulmonary arrest or sudden death and to report any history of coronary artery disease, congestive heart failure, or arrhythmias [see Warnings and Precautions (5.2)].

Pulmonary Toxicity

Advise patients to contact their healthcare provider immediately for new or worsening cough, chest pain, or shortness of breath [see Warnings and Precautions (5.3)].

Dermatologic Toxicities

Advise patients to limit sun exposure during ERBITUX treatment and for 2 months after the last dose of ERBITUX. Advise patients to notify their healthcare provider of any sign of acne-like rash, (which can include itchy, dry, scaly, or cracking skin and inflammation, infection or swelling at the base of the nails or loss of the nails), conjunctivitis, blepharitis, or decreased vision [see Warnings and Precautions (5.4)].

Embryo-Fetal Toxicity

Advise female patients of reproductive potential of the potential risk to a fetus and to use effective contraception during ERBITUX treatment and for 2 months after the last dose of ERBITUX. Advise patients to inform their healthcare provider of a known or suspected pregnancy [see Warnings and Precautions (5.8), Use in Specific Populations (8.3)].

Lactation

Advise patients not to breastfeed during ERBITUX treatment and for 2 months after the last dose of ERBITUX [see Use in Specific Populations (8.2)].

ERBITUX® is a registered trademark of ImClone LLC a wholly-owned subsidiary of Eli Lilly and Company.

Manufactured by ImClone LLC a wholly-owned subsidiary of Eli Lilly and Company, Branchburg, NJ 08876 USA

Eli Lilly and Company, Indianapolis, IN 46285, USA
US License No. 1827

Copyright © 2004, 2021, ImClone LLC a wholly-owned subsidiary of Eli Lilly and Company. All rights reserved.

ERB-0009-USPI-20210927