ERBITUX

Cetuximab is a recombinant chimeric human/mouse IgG1 monoclonal antibody that competitively binds to epidermal growth factor receptor (EGFR) and competitively inhibits the binding of epidermal growth factor (EGF).

EGFR is a member of the

ErbB family of receptor tyrosine kinases found in both normal and tumour cells; it is responsible for regulating epithelial tissue development and homeostasis.

EGFR has been implicated in various types of cancer, as it is often overexpressed in malignant cells and EGFR overexpression has been linked to more advanced disease and poor prognosis.

EGFR is often mutated in certain types of cancer and serves as a driver of tumorigenesis.

In vitro, cetuximab was shown to mediate anti-tumour effects in numerous cancer cell lines and human tumour xenografts.

Approved by the FDA in

February 2004 under the brand name ERBITUX, cetuximab is used for the treatment of head and neck cancer and metastatic, KRAS wild-type colorectal cancer, and metastatic colorectal cancer with a BRAF V600E mutation. 3, 13 It has also been investigated in advanced colorectal cancer, EGFR-expressing non-small cell lung cancer (NSCLC), and unresectable squamous cell skin cancer.

Cetuximab is administered via intravenous infusion and is used as monotherapy or in combination with other chemotherapies, including platinum agents, radiation therapy, leucovorin, fluorouracil, and irinotecan.

Cetuximab is indicated for

The treatment of locally or regionally advanced squamous cell carcinoma of the head and neck in combination with radiation therapy.

The treatment of recurrent locoregional disease or metastatic squamous cell carcinoma of the head and neck in combination with platinum-based therapy with fluorouracil.

The treatment of recurrent or metastatic squamous cell carcinoma of the head and neck progressing after platinum-based therapy.

K-Ras wild-type, EGFR-expressing, metastatic colorectal cancer as determined by an FDA-approved test in combination with FOLFIRI, a chemotherapy combination that includes leucovorin, fluorouracil, and irinotecan In combination with irinotecan in patients who are refractory to irinotecan-based chemotherapy; or as monotherapy in patients who have failed oxaliplatin.

• and irinotecan-based chemotherapy or who are intolerant to irinotecan.

Metastatic colorectal cancer that is BRAF

V600E mutation-positive (as determined by an FDA-approved test) in combination with encorafenib but only after prior therapy.

Cetuximab is not indicated for the treatment of Ras-mutant colorectal cancer or when the results of the Ras mutation tests are unknown.

Cetuximab is an anticancer agent that works by inhibiting the growth and survival of epidermal growth factor receptor (EGFR)-expressing tumour cells with high specificity and higher affinity than epidermal growth factor (EGF) and transforming growth factor-alpha (TGF-α), which are natural ligands of EGFR.

Cetuximab works by inhibiting the growth and survival of EGFR-positive tumours.

In vitro, it promotes antibody-dependent cellular cytotoxicity (ADCC) against certain human tumour types.

On the contrary, cetuximab does not exert its anti-tumour effects on human tumour xenografts lacking EGFR expression. 3, 11 Cetuximab potentiates the cytotoxic effects of chemotherapeutics and radiation therapy when used in combination.

In human tumour xenograft models in mice, cetuximab and irinotecan synergistically inhibited the growth of orthotopic anaplastic thyroid carcinoma xenografts in vitro and in vivo.

Cetuximab potentiated the in vitro anti-proliferative and pro-apoptotic effect of irinotecan and achieved 93% in vivo inhibition of tumour growth when combined with irinotecan, compared to 77% and 79% inhibition when cetuximab and irinotecan were used alone, respectively.

After administration of a 400 mg/m 2 initial dose followed by a 250 mg/m 2 weekly dose, the steady-state levels of cetuximab was reached by the third weekly infusion with mean peak and trough concentrations across studies ranging from 168 µg/mL to 235 µg/mL and 41 µg/mL to 85 µg/mL, respectively.

T max is about 3 hours.

The volume of the distribution is about 2-3 L/m and is independent of dose.

Like other monoclonal antibodies, cetuximab is expected to undergo lysosomal degradation by the reticuloendothelial system and protein catabolism by a target‐mediated disposition pathway.

There is limited information available.

After administration of a 400 mg/m 2 initial dose followed by a 250 mg/m 2 weekly dose, the mean half-life for cetuximab was approximately 112 hours, with a range of 63-230 hours.

In patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck, the estimated clearance rate was 0.103 L/h.

At doses ranging from 200-400 mg/m 2, complete saturation of systemic clearance was observed.

In a population pharmacokinetic study, female patients had a 25% lower intrinsic cetuximab clearance than male patients, although there was no evidence of the need for dose modification based on sex.

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The intravenous

LD is > 300 mg/kg in mice and > 200 mg/kg in rats.

There is limited information on the overdose from cetuximab.

In clinical trials, cetuximab was associated with serious and fatal infusion reactions, cardiopulmonary arrest or sudden death, and serious dermatologic toxicities.

Pulmonary toxicities, such as interstitial lung disease, interstitial pneumonitis with non-cardiogenic pulmonary edema, and exacerbation of pre-existing fibrotic lung disease have been reported.

Premedicate with an

H 1 receptor antagonist.

Initial dose: 400 mg/m 2 administered as a 120-minute intravenous infusion one week prior to initiating a course of radiation therapy.

Subsequent doses: 250 mg/m 2 administered as a 60-minute infusion every week for the duration of radiation therapy (6–7 weeks).

ERBITUX administration 1 hour prior to radiation therapy.

As Single-Agent or in Combination With Chemotherapy: Weekly: Administer initial dose of 400 mg/m as a 120-minute intravenous infusion, and subsequent doses of 250 mg/m 2 infused over 60 minutes once weekly.

Administer 500 mg/m as a 120-minute intravenous infusion every two weeks.

ERBITUX administration 1 hour prior to chemotherapy.

Continue treatment until disease progression or unacceptable toxicity.

See full prescribing information for dosage adjustments for adverse reactions. 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, or BRAF V600E mutation-positive metastatic CRC 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: 2.2 Recommended Dosage for Squamous Cell Carcinoma of the Head and Neck (SCCHN) In combination with radiation therapy Initial dose: 400 mg/m 2 administered as a 120-minute intravenous infusion one week prior to initiating a course of radiation therapy.

As a single-agent or in combination with platinum-based therapy and fluorouracil Administer Erbitux as a single-agent or in combination with platinum-based therapy and fluorouracil on a weekly or biweekly schedule.

Initial dose: 400 mg/m 2 administered as a 120-minute intravenous infusion Subsequent doses: 250 mg/m 2 administered as a 60-minute infusion every week Biweekly Dosage Initial and subsequent doses: 500 mg/m 2 administered as a 120-minute intravenous infusion every 2 weeks Complete ERBITUX administration 1 hour prior to platinum-based therapy with fluorouracil.

Continue treatment until disease progression or unacceptable toxicity. 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.

Initial dose: 400 mg/m 2 administered as a 120-minute intravenous infusion Subsequent doses: 250 mg/m 2 administered as a 60-minute infusion every week Biweekly Dosage Initial and subsequent doses: 500 mg/m 2 administered as a 120-minute intravenous infusion every 2 weeks Complete ERBITUX administration 1 hour prior to irinotecan or FOLFIRI.

In combination with encorafenib

The recommended initial dose is 400 mg/m 2 administered as a 120-minute intravenous infusion in combination with encorafenib.

The recommended subsequent dosage is 250 mg/m 2 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 (H 1 ) receptor antagonist intravenously 30–60 minutes prior to the first dose or subsequent doses as deemed necessary. 2.5 Dosage Modifications for Adverse Reactions Reduce, delay, or discontinue ERBITUX to manage adverse reactions as described in Table 1.

Table 1: Recommended Dosage Modifications for Adverse Reactions Adverse Reaction Severity a Dosage Modification a National Cancer Institute (NCI) Common Toxicity Criteria (CTC), version 2.0.

Infusion reactions

Grade 1 or 2 Reduce the infusion rate by 50%.

Grade 3 or 4 Immediately and permanently, discontinue ERBITUX.

Dermatologic toxicities and infectious sequelae (e.g., acneiform rash, mucocutaneous disease) 1 st occurrence; Grade 3 or 4 Delay infusion to 2 weeks; if condition improves, continue at 250 mg/m 2.

If no improvement, discontinue ERBITUX. 2 nd occurrence; Grade 3 or 4 Delay infusion to 2 weeks; if condition improves, continue at 200 mg/m 2.

If no improvement, discontinue ERBITUX. 3 rd occurrence; Grade 3 or 4 Delay infusion to 2 weeks; if condition improves, continue at 150 mg/m 2.

If no improvement, discontinue ERBITUX. 4 th occurrence; Grade 3 or 4 Discontinue ERBITUX.

Pulmonary toxicity Acute onset or worsening pulmonary symptoms Delay infusion to 2 weeks; if condition improves, continue at the dose that was being administered at the time of occurrence.

If no improvement in 2 weeks or interstitial lung disease (ILD) is confirmed, discontinue ERBITUX. 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.

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.

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.

Based on findings from animal studies 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.

IgG is known to cross the placental barrier; therefore, cetuximab may be transmitted from the mother to the developing fetus.

Advise pregnant women of the potential risk to a fetus.

In the

U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is to 4% and to 20% respectively.

Pregnant cynomolgus monkeys were administered cetuximab intravenously once weekly during the period of organogenesis (gestation day [GD] 20-48) at dose levels 0.4 to 4 times the recommended dose of ERBITUX based on body surface area (BSA).

Cetuximab was detected in the amniotic fluid and in the serum of embryos from treated dams on GD 49.

While no fetal malformations occurred in offspring, there was an increased incidence of embryolethality and abortions at doses approximately to 4 times the recommended dose of ERBITUX based on BSA.

In mice, EGFR is critically important in reproductive and developmental processes including blastocyst implantation, placental development, and embryo-fetal/postnatal survival and development.

Reduction or elimination of embryo-fetal or maternal EGFR signaling can prevent implantation, can cause embryo-fetal loss during various stages of gestation (through effects on placental development), and can cause developmental anomalies and early death in surviving fetuses.

Adverse developmental outcomes were observed in multiple organs in embryos/neonates of mice with disrupted EGFR signaling.

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/m 2, to 27 patients ranging from to 12 years old; and in 19 patients ranging from 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/m and 150 mg/m 2.

The volume of the distribution appears to be independent of dose and approximates the vascular space of 2 L/m to 3 L/m 2.

Following a single dose of 250 mg/m 2, the mean AUC 0-inf (CV%) was 17.7 mgh/mL (34%) in the younger (1–12 years, n=9) and 13.4 mgh/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.

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 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.

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