Necitumumab (Monograph)

Brand name: Portrazza
Drug class: Antineoplastic Agents
- Epidermal Growth Factor Receptor Inhibitors
- EGFR Inhibitors
- EGF Receptor Inhibitors
ATC class: L01XC22
VA class: AN900
Chemical name: Disulfide with human monoclonal IMC-11F8 κ-chain anti-(human epidermal growth factor receptor) (human monoclonal IMC-11F8 γ1-chain) immunoglobulin G1 dimer
Molecular formula: C₆₄₃₆H₉₉₅₈N₁₇₀₂O₂₀₂₀S₄₂
CAS number: 906805-06-9

Introduction

Antineoplastic agent; a recombinant, fully human IgG₁ kappa monoclonal antibody that binds to human epidermal growth factor receptor (EGFR).^{1 2 4 5 6}

Uses for Necitumumab

Non-small Cell Lung Cancer (NSCLC)

Used in combination with gemcitabine and cisplatin for first-line treatment of metastatic squamous NSCLC;^{1 2 4} designated an orphan drug by FDA for this cancer.⁹

In combination with gemcitabine and cisplatin, substantially prolonged median overall survival (11.5 versus 9.9 months) and progression-free survival (5.7 versus 5.5 months) compared with gemcitabine and cisplatin alone in patients with chemotherapy-naive metastatic squamous NSCLC.^{1 2}

No difference in overall survival, progression-free survival, or overall response rate observed in patients with nonsquamous NSCLC treated with necitumumab in combination with pemetrexed and cisplatin compared with pemetrexed and cisplatin alone.^{1 3}

Manufacturer states not indicated for treatment of nonsquamous NSCLC^{† [off-label]}.¹ (See Increased Toxicity and Mortality in Nonsquamous NSCLC under Cautions.)

Necitumumab Dosage and Administration

General

Premedication for Infusion-related Reactions

• In patients who previously experienced a grade 1 or 2 infusion-related reaction to necitumumab, premedicate with an antihistamine (e.g., diphenhydramine or equivalent) prior to each subsequent infusion.¹

• Following a second occurrence of a grade 1 or 2 infusion-related reaction, premedicate with an antihistamine (e.g., diphenhydramine or equivalent), acetaminophen (or equivalent), and dexamethasone (or equivalent) prior to each subsequent infusion.¹ (See Infusion-related Reactions under Dosage and Administration and also under Cautions.)

Serum Electrolyte Monitoring

• Closely monitor serum electrolyte concentrations, including magnesium, potassium, and calcium, and aggressively correct electrolyte abnormalities as clinically appropriate prior to each necitumumab infusion and for ≥8 weeks following the last dose.¹ (See Electrolyte Abnormalities under Dosage and Administration.)

Administration

IV Administration

For solution compatibility information, see Compatibility under Stability.

Administer by IV infusion via an infusion pump.¹

Necitumumab injection concentrate must be diluted prior to administration.¹ Use within 4 hours following dilution if stored at room temperature or within 24 hours if stored at 2–8°C.¹ (See Storage under Stability.)

Do not administer with any other drug or electrolytes simultaneously in the same IV line.¹

Flush IV line with 0.9% sodium chloride injection at end of infusion.¹

Dilution

Withdraw appropriate volume of necitumumab injection concentrate from vial labeled as containing 800 mg in 50 mL and add to infusion container containing the appropriate volume of 0.9% sodium chloride injection to yield a final volume of 250 mL.¹ Mix by gentle inversion; do not shake.¹

Do not dilute in dextrose-containing or other solutions or admix with any other drug or electrolytes.¹

Discard any partially used vials.¹

Rate of Administration

Administer over 60 minutes.¹

Dosage

Adults

NSCLC

IV

800 mg on days 1 and 8 of each 3-week cycle; use in combination with gemcitabine and cisplatin.¹

Administer necitumumab prior to IV infusion of gemcitabine and cisplatin.¹

Continue therapy until disease progression or unacceptable toxicity occurs.¹

Dosage Modification

Infusion-related Reactions

If grade 1 infusion-related reaction occurs, reduce infusion rate by 50%.¹

If grade 2 infusion-related reaction occurs, interrupt infusion until resolution to grade 1 or less; resume at 50% reduced rate for subsequent infusions.¹

If grade 3 or 4 infusion-related reaction occurs, permanently discontinue therapy.¹ (See Infusion-related Reactions under Cautions.)

Dermatologic Toxicity

If grade 3 rash or acneiform rash develops, interrupt therapy.¹ If toxicity improves to grade 2 or less, resume necitumumab at reduced dosage of 400 mg for at least 1 cycle.¹ May increase dosage to 600 mg, then to 800 mg in subsequent cycles if symptoms do not worsen.¹ If dermatologic toxicity worsens or becomes intolerable at a dosage of 400 mg, permanently discontinue therapy.¹ If grade 3 rash or acneiform rash does not improve to grade 2 or less within 6 weeks, permanently discontinue therapy.¹

If grade 3 skin induration/fibrosis or grade 4 dermatologic toxicity occurs, permanently discontinue therapy.¹ (See Dermatologic Toxicity under Cautions.)

Electrolyte Abnormalities

If grade 3 or 4 electrolyte abnormalities occur, interrupt therapy.¹ Resume therapy at previous dosage upon improvement of hypomagnesemia and related electrolyte abnormalities to grade 2 or less.¹ (See Cardiopulmonary Arrest and also see Hypomagnesemia under Cautions.)

Special Populations

Hepatic Impairment

No specific dosage recommendations at this time.¹ (See Hepatic Impairment under Cautions.)

Renal Impairment

No specific dosage recommendations at this time.¹ (See Renal Impairment under Cautions.)

Geriatric Patients

No specific dosage recommendations at this time.¹ (See Geriatric Use under Cautions.)

Body Weight, Race, and Gender

No dosage adjustment required.¹ (See Special Populations under Pharmacokinetics.)

Cautions for Necitumumab

Contraindications

• Manufacturer states none known.¹

Warnings/Precautions

Warnings

Cardiopulmonary Arrest

Cardiopulmonary arrest and/or sudden death occurred in 3% of patients receiving necitumumab in combination with gemcitabine and cisplatin for treatment of metastatic squamous NSCLC in the principal efficacy study.¹ Majority of patients died within 30 days of the last dose of necitumumab and had comorbid conditions (e.g., CAD, hypomagnesemia, COPD, hypertension).¹ Incremental risk of cardiopulmonary arrest or sudden death with necitumumab therapy in patients with a history of CAD, CHF, or arrhythmias compared with those without these cardiovascular conditions not known.¹

Closely monitor serum electrolytes, including magnesium, potassium, and calcium, prior to each necitumumab infusion and for ≥8 weeks after the last dose.¹ Withhold therapy for grade 3 or 4 electrolyte abnormalities.¹ Aggressively correct electrolyte abnormalities as clinically appropriate.¹

Hypomagnesemia

Hypomagnesemia occurred in 83% of patients and was severe (grade 3 or 4) in 20% of patients receiving necitumumab in combination with gemcitabine and cisplatin in the primary efficacy study.¹ Median time to development of hypomagnesemia and accompanying electrolyte abnormalities was 6 weeks following initiation of therapy.¹

Monitor serum electrolytes, including magnesium, potassium, and calcium, prior to each necitumumab infusion and for ≥8 weeks after completion of therapy.¹ Correct electrolyte abnormalities as clinically appropriate.¹ Withhold necitumumab therapy for grade 3 or 4 electrolyte abnormalities.¹

Other Warnings and Precautions

Thromboembolic Events

Increased risk of thromboembolic events.¹ Venous and arterial thromboembolic events (e.g., PE, DVT, stroke/cerebral ischemia, MI), including fatal cases, reported.¹ Relative risk approximately threefold higher in patients with a history of thromboembolic events than in patients without such history.¹

If a serious or life-threatening venous or arterial thromboembolic event occurs, permanently discontinue therapy.¹

Dermatologic Toxicity

Dermatologic toxicity, including rash, acneiform dermatitis, acne, dry skin, pruritus, generalized rash, skin fissures, maculopapular rash, and erythema, reported in 79% of necitumumab-treated patients in the principal efficacy study and was severe in 8% of patients.¹ Dermatologic toxicity usually developed within first 2 weeks of therapy and resolved ≤17 weeks after onset.¹

Limit sun exposure.¹ (See Advice to Patients.)

If dermatologic toxicity occurs, dosage reduction or discontinuance of therapy may be necessary.¹ (See Dermatologic Toxicity under Dosage and Administration.)

Infusion-related Reactions

Infusion-related reactions occurred in 1.5% and grade 3 infusion-related reactions occurred in 0.4% of necitumumab-treated patients in the primary efficacy study.¹ Most infusion-related reactions occurred after the first or second infusion of the drug.¹ None of the patients received premedication for infusion-related reactions for the first dose of necitumumab in this study.¹

Monitor patients for manifestations of infusion-related reaction during and following necitumumab infusions.¹ If infusion-related reactions occur, administer premedication before all subsequent infusions.¹ (See Premedication for Infusion-related Reactions under Dosage and Administration.) Reduction in infusion rate or discontinuance of therapy may be necessary depending on severity of the reaction.¹ (See Infusion-related Reactions under Dosage and Administration.)

Increased Toxicity and Mortality in Nonsquamous NSCLC

Increased incidence of serious toxicity and mortality reported in patients with nonsquamous NSCLC.^{1 3} Serious toxicity, fatal toxicity, and cardiopulmonary arrest and/or sudden death reported in more patients with nonsquamous NSCLC receiving necitumumab in combination with pemetrexed and cisplatin compared with those receiving pemetrexed and cisplatin alone.¹

Necitumumab is not indicated for the treatment of nonsquamous NSCLC^{† [off-label]}.¹

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm; developmental toxicity, embryolethality, and postnatal deaths demonstrated in animals.¹

Avoid pregnancy during therapy.¹ Women of childbearing potential should use effective contraception during therapy and for 3 months after drug discontinuance.¹ If used during pregnancy or if patient becomes pregnant, apprise of potential fetal hazard.¹

Specific Populations

Pregnancy

May cause fetal harm.¹ (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Lactation

Not known whether necitumumab is distributed into milk.¹ Women should not breast-feed during therapy and for 3 months after the last dose.¹

Pediatric Use

Safety and efficacy not established in pediatric patients.¹

Geriatric Use

In the principal efficacy study in NSCLC, 39% of patients were ≥65 years of age and 20% were ≥70 years of age.¹ In a subgroup analysis, overall survival benefit not observed in patients ≥70 years of age receiving necitumumab in combination with gemcitabine and cisplatin.^{1 2} Although overall safety of necitumumab was generally similar for subgroups of patients <70 years of age and those ≥70 years of age, a higher incidence of venous thromboembolic events, including PE, observed in patients ≥70 years of age.^{1 2} (See Special Populations under Pharmacokinetics.)

Hepatic Impairment

Formal studies evaluating the effect of hepatic impairment on the pharmacokinetics of necitumumab not conducted to date.¹ In a population pharmacokinetic analysis, systemic exposure not affected by mild or moderate hepatic impairment.¹ No patients with severe hepatic impairment were enrolled in clinical trials.¹

Renal Impairment

Not formally studied, but systemic exposure does not appear to be affected by renal function.^{1 10} (See Special Populations under Pharmacokinetics.)

Common Adverse Effects

Hypomagnesemia,^{1 2} hypocalcemia,¹ rash,^{1 2} hypophosphatemia,¹ vomiting,¹ hypokalemia,¹ diarrhea,¹ acneiform dermatitis.¹

Drug Interactions

Specific Drugs

Necitumumab Pharmacokinetics

Absorption

Bioavailability

Steady-state concentrations predicted to be reached approximately 100 days following IV infusion of necitumumab 800 mg on days 1 and 8 of each 21-day cycle.¹

Special Populations

Systemic exposure not affected by renal function in a population pharmacokinetic analysis.¹

Systemic exposure not affected by mild or moderate hepatic impairment in a population pharmacokinetic analysis.¹ Patients with severe hepatic impairment not enrolled in clinical trials.¹

Gender, age (range: 19–84 years), and race do not substantially affect systemic exposure.¹

Effect of body weight on necitumumab exposure not clinically important.¹ (See Special Populations under Dosage and Administration.)

Distribution

Extent

Not known whether necitumumab distributes into milk.¹

Elimination

Half-life

Approximately 14 days.¹

Stability

Storage

Parenteral

Injection

2–8°C.¹ Keep vial in outer carton until time of use to protect from light; do not freeze or shake vial.¹

Diluted infusion solution: Room temperature (≤25°C) for ≤4 hours or 2–8°C for ≤24 hours after dilution.¹ Do not freeze or shake infusion solution.¹

Compatibility

Dilute in 0.9% sodium chloride.¹

Do not dilute with dextrose-containing or other solutions or admix with other drugs or electrolytes.¹

Parenteral

Solution Compatibility

Actions

• A recombinant, fully human IgG₁ kappa monoclonal antibody that binds with high affinity and specificity to human EGFR.^{1 2 4 5 6 7 10}

• Necitumumab's mechanism of EGFR inhibition appears similar to that of cetuximab.^{5 6 8}

• Necitumumab competitively blocks the interaction of EGFR with its ligands, resulting in inhibition of ligand-induced phosphorylation and downstream signaling pathways, which play an important role in cell proliferation, invasion, metastasis, angiogenesis, and inhibition of apoptosis.^{1 4 5 7 10}

• Binding of necitumumab induces EGFR internalization and degradation in vitro; in vitro binding also leads to antibody-dependent cell-mediated cytotoxicity (ADCC) in EGFR-expressing cells.^{1 4 5 10}

• In mice bearing xenografts of human cancer, including NSCLC, necitumumab in combination with gemcitabine and cisplatin resulted in increased antitumor activity compared with gemcitabine and cisplatin alone.^{1 4 5 10}

Advice to Patients

• Risk of electrolyte abnormalities, including hypomagnesemia, hypokalemia, and hypocalcemia.¹ Importance of advising patients to take electrolyte replacement therapy exactly as advised by their clinician.¹

• Risk of venous and arterial thromboembolic events.¹

• Risk of skin reactions.¹ Importance of minimizing sun exposure with protective clothing and use of sunscreen during therapy.¹

• Risk of infusion-related reactions.¹ Importance of informing patients to report signs and symptoms of infusion reactions (e.g., fever, chills, breathing problems) to a healthcare professional.¹

• Risk of fetal harm.¹ Advise women of childbearing potential to use effective methods of contraception while receiving necitumumab and for 3 months after the last dose.¹ If pregnancy occurs, apprise patient of potential fetal hazard.¹

• Importance of advising women to avoid breast-feeding during therapy and for 3 months following the last dose.¹

• Importance of informing patients of other important precautionary information.¹ (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

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