Necitumumab Intravenous

Non-small Cell Lung Cancer

Necitumumab is used in combination with gemcitabine and cisplatin for the first-line treatment of metastatic squamous non-small cell lung cancer (NSCLC).^[1][2][4] Necitumumab is designated an orphan drug by FDA for the treatment of this cancer.^[9]

The current indication for necitumumab in the treatment of metastatic squamous NSCLC is based principally on the results of a randomized, multinational, open-label, controlled phase 3 study (SQUIRE) in adults with chemotherapy-naive metastatic (stage IV) squamous NSCLC.^[1][2] In this study, 1093 patients were randomized (stratified by ECOG performance status and race) in a 1:1 ratio to receive either necitumumab (800 mg by IV infusion on days 1 and 8) in combination with gemcitabine (1.25 g/m² by IV infusion on days 1 and 8) and cisplatin (75 mg/m² by IV infusion on day 1) or gemcitabine in combination with cisplatin every 3 weeks for a maximum of 6 cycles in the absence of disease progression or unacceptable toxicity.^[1][2] Patients demonstrating at least stable disease while receiving necitumumab, gemcitabine, and cisplatin continued to receive necitumumab as single-agent therapy until disease progression or unacceptable toxicity occurred.^[1][2] The primary measure of efficacy was overall survival; secondary end points included overall response rate and investigator-assessed progression-free survival.^[1][2] The median age of patients was 62 years (range: 32-86 years), 83% were male, 84% were Caucasian, and most were smokers (91%).^[1] Baseline ECOG performance status was 0 or 1 for 91% of the patients and 2 for the remaining 9% of the patients; 91% of the patients had metastatic disease in 2 or more sites.^[1][2] The median duration of follow-up was approximately 25 months.^[2] Patients receiving necitumumab in combination with gemcitabine and cisplatin had a substantially longer median overall survival (11.5 versus 9.9 months) and investigator-assessed progression-free survival (5.7 versus 5.5 months) compared with patients receiving gemcitabine and cisplatin alone.^[1][2] No significant difference in overall response rate was observed between the 2 treatment groups in this study (31 versus 29%, respectively).^[1][2]

In a randomized, open-label, multicenter phase 3 study (INSPIRE) in adults with chemotherapy-naive metastatic nonsquamous NSCLC, patients were randomized to receive either necitumumab in combination with pemetrexed and cisplatin or pemetrexed and cisplatin alone every 3 weeks.^[1][3] This study was terminated prematurely because an increased incidence of death due to any cause and of thromboembolic events was observed in the group of patients treated with necitumumab, pemetrexed, and cisplatin.^[1][3] At the time of study termination, 633 patients had been enrolled; the median age of patients was 61 years and 89% had adenocarcinoma histology.^[1] The median duration of follow-up for the necitumumab plus pemetrexed and cisplatin and the pemetrexed and cisplatin alone groups was 24.5 and 25.6 months, respectively.^[3] The addition of necitumumab to pemetrexed and cisplatin was not found to improve overall survival (the primary measure of efficacy), progression-free survival, or overall response rate in this study.^[1][3]

The manufacturer states that necitumumab is not indicated for the treatment of nonsquamous NSCLC^† .^[1] (See Increased Toxicity and Mortality in Nonsquamous NSCLC under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)

General

To minimize the risk of infusion-related reactions in patients who have previously experienced a grade 1 or 2 infusion-related reaction to necitumumab, premedication with an antihistamine (e.g., diphenhydramine or equivalent) is recommended prior to all subsequent infusions of the drug.^[1] Patients who have experienced a second occurrence of a grade 1 or 2 infusion-related reaction should receive an antihistamine (diphenhydramine or equivalent), acetaminophen (or equivalent), and dexamethasone (or equivalent) prior to each subsequent necitumumab infusion.^[1] (See Infusion-related Reactions under Dosage: Dosage Modification for Toxicity, in Dosage and Administration and also under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)

Serum electrolyte concentrations, including magnesium, potassium, and calcium, should be monitored closely and electrolyte abnormalities corrected aggressively, as clinically appropriate, prior to each infusion of necitumumab and for at least 8 weeks following the last dose of the drug.^[1] (See Electrolyte Abnormalities under Dosage: Dosage Modification for Toxicity, in Dosage and Administration.)

Administration

Necitumumab is administered by IV infusion over 60 minutes; the infusion solution should be administered using an infusion pump.^[1] Diluted necitumumab infusion solution should not be administered in the same IV line with any other drug or electrolytes.^[1] The IV line should be flushed with 0.9% sodium chloride injection at the end of the infusion.^[1]

Necitumumab injection concentrate must be diluted prior to administration.^[1] Prior to dilution, the injection concentrate should be inspected visually for particulate matter and discoloration.^[1] The injection concentrate should be clear to slightly opalescent and colorless to slightly yellow and should not be used if particulate matter or discoloration is present.^[1]

Necitumumab is diluted by adding the appropriate volume of necitumumab injection concentrate (containing 16 mg/mL) to an infusion container containing the appropriate volume of 0.9% sodium chloride injection to yield a final volume of 250 mL.^[1] Necitumumab injection concentrate should not be diluted with solutions containing dextrose or other solutions.^[1] Necitumumab also should not be admixed with any other drug or electrolytes.^[1] The diluted necitumumab infusion solution should be mixed by gentle inversion and should not be shaken.^[1] Diluted necitumumab infusion solution may be stored at room temperature (up to 25°C) for up to 4 hours or under refrigeration (2-8°C) for up to 24 hours; the diluted infusion solution should not be frozen.^[1]

Diluted necitumumab infusion solution should be inspected visually for particulate matter and discoloration prior to administration; if particulate matter or discoloration is evident, the diluted solution should be discarded.^[1]

Any unused portion left in the vial should be discarded since necitumumab injection concentrate contains no preservative.^[1]

Unopened vials of necitumumab injection concentrate should be protected from light and stored in the original carton at 2-8°C, and should not be frozen or shaken.^[1]

Dosage

Non-small Cell Lung Cancer

For the first-line treatment of metastatic squamous non-small cell lung cancer (NSCLC), the recommended adult dosage of necitumumab is 800 mg administered as a 60-minute IV infusion on days 1 and 8 of each 3-week cycle.^[1] The drug is given in combination with gemcitabine and cisplatin.^[1]

Necitumumab should be administered by IV infusion prior to IV infusion of gemcitabine and cisplatin.^[1]

Treatment with necitumumab should be continued until disease progression or unacceptable toxicity occurs.^[1]

Dosage Modification for Toxicity

Infusion-related Reactions

If a grade 1 infusion-related reaction occurs, the infusion rate should be reduced by 50% for the duration of the infusion.^[1]

If a grade 2 infusion-related reaction occurs, the infusion should be interrupted until resolution to grade 1 or less; the infusion should then be resumed at a 50% reduced infusion rate for all subsequent infusions.^[1]

If grade 3 or 4 infusion-related reactions occur, necitumumab should be permanently discontinued.^[1] (See Infusion-related Reactions under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)

Dermatologic Toxicity

If grade 3 rash or acneiform rash develops, necitumumab therapy should be withheld.^[1] If toxicity improves to grade 2 or less, the drug should be resumed at a reduced dosage of 400 mg for at least 1 treatment cycle.^[1] If symptoms do not worsen, the dosage may be increased to 600 mg and then to 800 mg in subsequent cycles.^[1] If dermatologic toxicity worsens or becomes intolerable at a dosage of 400 mg, necitumumab therapy should be permanently discontinued.^[1] If grade 3 rash or acneiform rash does not improve to grade 2 or less within 6 weeks of withholding necitumumab, therapy should be permanently discontinued.^[1]

If grade 3 skin induration/fibrosis or grade 4 dermatologic toxicity occurs, necitumumab therapy should be permanently discontinued.^[1] (See Dermatologic Toxicity under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)

Electrolyte Abnormalities

If grade 3 or 4 electrolyte abnormalities occur, necitumumab therapy should be withheld until resolution to grade 2 or less; treatment may be resumed at the previous dosage upon improvement of hypomagnesemia and related electrolyte abnormalities to grade 2 or less.^[1] (See Cardiopulmonary Arrest and also see Hypomagnesemia under Warnings/Precautions: Warnings, in Cautions.)

Special Populations

The manufacturer provides no specific dosage recommendations for geriatric patients or for patients with hepatic or renal impairment.^[1] (See Specific Populations under Cautions: Warnings/Precautions.)

No dosage adjustment is necessary based on body weight, race, or gender.^[1]

Contraindications

The manufacturer states there are no contraindications to the use of necitumumab.^[1]

Warnings/Precautions

Warnings

Cardiopulmonary Arrest

Cardiopulmonary arrest and/or sudden death occurred in 15 (3%) of 538 patients receiving necitumumab in combination with gemcitabine and cisplatin compared with 3 (0.6%) of 541 patients receiving gemcitabine and cisplatin alone for metastatic squamous non-small cell lung cancer (NSCLC) in the primary efficacy study.^[1] Twelve of the 15 patients died within 30 days of the last dose of necitumumab and had comorbid conditions (including 3 patients with a history of coronary artery disease, 4 with hypomagnesemia, 7 with chronic obstructive pulmonary disease, and 5 with hypertension); 11 of the 12 patients had an unwitnessed death.^[1] Patients with substantial coronary artery disease, myocardial infarction within 6 months, uncontrolled hypertension, and uncontrolled congestive heart failure were excluded from this study.^[1] The incremental risk of cardiopulmonary arrest or sudden death with necitumumab therapy in patients with a history of coronary artery disease, congestive heart failure, or arrhythmias compared with those without these cardiovascular conditions is not known.^[1]

Serum electrolyte concentrations, including magnesium, potassium, and calcium, should be closely monitored prior to each necitumumab infusion and for at least 8 weeks following the last dose of the drug.^[1] Necitumumab therapy should be withheld for grade 3 or 4 electrolyte abnormalities.^[1] (See Electrolyte Abnormalities under Dosage: Dosage Modification for Toxicity, in Dosage and Administration.) Electrolyte abnormalities should be aggressively corrected, as clinically appropriate.^[1]

Hypomagnesemia

Hypomagnesemia occurred in 83% of patients receiving necitumumab in combination with gemcitabine and cisplatin compared with 70% of patients receiving gemcitabine and cisplatin alone in the primary efficacy study, and severe (grade 3 or 4) hypomagnesemia occurred in 20% of patients receiving necitumumab with gemcitabine and cisplatin compared with 7% of patients receiving gemcitabine and cisplatin alone.^[1] The median time to development of hypomagnesemia and accompanying electrolyte abnormalities was 6 weeks, and about half of the cases developed within 4-9 weeks following initiation of necitumumab therapy.^[1]

Serum electrolyte concentrations, including magnesium, potassium, and calcium, should be monitored prior to each necitumumab infusion during therapy and for at least 8 weeks following completion of therapy.^[1] If electrolyte abnormalities occur, they should be corrected, as clinically appropriate.^[1] Necitumumab therapy should be withheld for grade 3 or 4 electrolyte abnormalities.^[1] (See Electrolyte Abnormalities under Dosage: Dosage Modification for Toxicity, in Dosage and Administration.)

Other Warnings and Precautions

Thromboembolic Events

Venous and arterial thromboembolic events, including some fatal events, have been reported in patients receiving necitumumab in combination with gemcitabine and cisplatin.^[1] The most common venous thromboembolic events were pulmonary embolism and deep-vein thrombosis and the most common arterial thromboembolic events were stroke/cerebral ischemia and myocardial infarction.^[1] In the primary efficacy study, venous thromboembolism (VTE) was reported in 9 or 5% of patients and was grade 3 or higher in 5 or 3% of patients receiving necitumumab with chemotherapy or chemotherapy alone, respectively.^[1] The incidence of fatal events was similar between treatment groups.^[1] Arterial thromboembolism was reported in 5 or 4% of patients and was grade 3 or higher in 4 or 2% of patients receiving necitumumab with chemotherapy or chemotherapy alone, respectively.^[1] The relative risk of venous or arterial thromboembolic events was approximately threefold higher in patients with a history of thromboembolic events than in patients without such a history.^[1]

Necitumumab should be permanently discontinued in patients who develop a serious or life-threatening venous or arterial thromboembolic event.^[1]

Dermatologic Toxicity

Dermatologic toxicity, including rash, acneiform dermatitis, acne, dry skin, pruritus, generalized rash, skin fissures, maculopapular rash, and erythema, was reported in 79% of patients receiving necitumumab in combination with gemcitabine and cisplatin in the primary efficacy study.^[1] Severe dermatologic toxicity occurred in 8% of patients receiving this regimen.^[1] Dermatologic toxicity usually developed within the first 2 weeks of therapy and resolved within 17 weeks after onset.^[1]

Sun exposure should be limited during necitumumab therapy.^[1] (See Advice to Patients.)

Reduction in dosage or discontinuance of therapy may be required in patients who develop dermatologic toxicity.^[1] (See Dermatologic Toxicity under Dosage: Dosage Modification for Toxicity, in Dosage and Administration.)

Infusion-related Reactions

Infusion-related reactions of any severity occurred in 1.5% and grade 3 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]

Patients should be monitored for manifestations of infusion-related reactions during and following infusions of necitumumab.^[1] If infusion-related reactions occur, premedication should be given for all subsequent infusions.^[1] (See General under Dosage and Administration.) Reduction in the infusion rate, temporary interruption of therapy, or permanent discontinuance of necitumumab may be necessary depending on the severity of the reaction.^[1] (See Infusion-related Reactions under Dosage: Dosage Modification for Toxicity, in Dosage and Administration.)

Increased Toxicity and Mortality in Nonsquamous NSCLC

In the INSPIRE study in patients with nonsquamous NSCLC, necitumumab in combination with pemetrexed and cisplatin was associated with an increased incidence of serious toxicity and mortality compared with pemetrexed and cisplatin alone.^[1][3] In this study, more patients receiving necitumumab in combination with pemetrexed and cisplatin compared with those receiving pemetrexed and cisplatin alone experienced serious toxicity (51 versus 41%, respectively), fatal toxicity (16 versus 10%), and cardiopulmonary arrest and/or sudden death (3.3 versus 1.3%).^[1] (See Uses: Non-small Cell Lung Cancer.)

The manufacturer states that necitumumab is not indicated for the treatment of nonsquamous NSCLC^† .^[1]

Fetal/Neonatal Morbidity and Mortality

Based on animal studies and its mechanism of action, necitumumab may cause fetal harm if administered to pregnant women.^[1] Disruption or depletion of epidermal growth factor receptor (EGFR) in animal models has been shown to impair embryofetal development (including effects on placental, lung, cardiac, skin, and neural development).^[1] The absence of EGFR signaling has resulted in embryolethality and postnatal deaths in animals.^[1] Women of childbearing potential should use effective contraception while receiving necitumumab and for 3 months after the final dose of the drug.^[1] If necitumumab is used during pregnancy or if the patient becomes pregnant while receiving the drug, the patient should be apprised of the potential fetal hazard.^[1]

Specific Populations

Pregnancy

Based on animal studies and its mechanism of action, necitumumab may cause fetal harm if administered to pregnant women.^[1] (See Fetal/Neonatal Morbidity and Mortality under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)

Lactation

It is not known whether necitumumab is distributed into human milk.^[1] The effects of the drug on nursing infants and on milk production also are unknown.^[1] Because of the potential for serious adverse reactions to necitumumab in nursing infants, women should be advised not to breast-feed while receiving the drug and for 3 months after the last dose.^[1]

Pediatric Use

Safety and efficacy of necitumumab have not been established in pediatric patients.^[1]

Geriatric Use

In the principal efficacy study evaluating necitumumab in patients with metastatic squamous NSCLC, 39% of patients were 65 years of age or older and 20% were 70 years of age or older.^[1] In a subgroup analysis of this study, an overall survival benefit was not observed in patients 70 years of age or older receiving necitumumab in combination with gemcitabine and cisplatin.^[1][2] Although the overall safety of necitumumab was generally similar for subgroups of patients younger than 70 years of age and those 70 years of age or older, a higher incidence of venous thromboembolic events, including pulmonary embolism, was observed in patients 70 years of age or older receiving necitumumab with gemcitabine plus cisplatin compared with younger patients in this study.^[1][2]

In a population pharmacokinetic analysis, patient age (range: 19-84 years) did not substantially affect systemic exposure of necitumumab.^[1]

Hepatic Impairment

Formal studies evaluating the effect of hepatic impairment on the pharmacokinetics of necitumumab have not been conducted to date.^[1] In a population pharmacokinetic analysis, systemic exposure to necitumumab was unaffected in patients with mild to moderate hepatic impairment.^[1] The manufacturer states that no patients with severe hepatic impairment were enrolled in clinical trials with the drug.^[1]

Renal Impairment

Formal studies evaluating the effect of renal impairment on the pharmacokinetics of necitumumab have not been conducted to date.^[10] However, a population pharmacokinetic analysis indicates that renal function (as assessed by estimated creatinine clearance in a range of 11-250 mL/minute) does not affect systemic exposure of the drug.^[1][10]

Common Adverse Effects

Adverse effects reported in at least 15% of patients receiving necitumumab in combination with gemcitabine and cisplatin in the primary efficacy study and at an incidence more than 2% higher than that reported with gemcitabine and cisplatin alone include rash,^[1][2] vomiting,^[1] diarrhea,^[1] and acneiform dermatitis.^[1]

Laboratory abnormalities reported in more than 10% of patients receiving necitumumab in combination with gemcitabine and cisplatin in the primary efficacy study and at an incidence more than 2% higher than that reported with gemcitabine and cisplatin alone include hypomagnesemia,^[1][2] hypokalemia,^[1] hypocalcemia,^[1] and hypophosphatemia.^[1]

Antineoplastic Agents

Concomitant use of necitumumab with gemcitabine and cisplatin in patients with advanced solid tumors increased peak plasma concentration and systemic exposure of gemcitabine by 63 and 22%, respectively, compared with administration of gemcitabine and cisplatin alone; systemic exposure to cisplatin was unchanged.^[1]

Concomitant use of necitumumab with gemcitabine and cisplatin did not substantially affect systemic exposure of necitumumab.^[1]

Necitumumab, a recombinant, fully human IgG₁ kappa monoclonal antibody that binds to human epidermal growth factor receptor (EGFR), is an antineoplastic agent.^{[1][2][4][5][6][7]}

Necitumumab binds with high affinity and specificity to the extracellular domain of the epidermal growth factor (EGF) binding site of human EGFR and competitively inhibits the interaction of EGFR with its ligands.^{[1][4][5][7][10]} The mechanism by which necitumumab inhibits EGFR appears to be similar to that of cetuximab, a recombinant chimeric (human-murine) monoclonal antibody used in the treatment of colorectal cancer and squamous cell carcinoma of the head and neck; cetuximab also has been used in the treatment of non-small cell lung cancer (NSCLC)^† .^[5][6][8] While EGFR-activating mutations are rare in squamous-cell histologic type cancers,^[2][7] overexpression of EGFR has been observed in the majority (60-80%) of these tumors.^[4][5][7] Blockade of EGFR results 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 (programmed cell death).^{[1][4][5][7][10]} Binding of necitumumab induces EGFR internalization and degradation in vitro; in addition, in vitro binding leads to antibody-dependent cell-mediated cytotoxicity (ADCC) in EGFR-expressing cells.^{[1][4][5][10]}

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

In contrast to cetuximab, which has been associated with hypersensitivity reactions in about 20% of patients when used for NSCLC^† , necitumumab is a fully human antibody and is therefore potentially less immunogenic.^[5][6] In the primary efficacy study of necitumumab in patients with metastatic squamous cell NSCLC, hypersensitivity/infusion-related reactions were reported in 1.5% of patients receiving the drug.^[1]

Based on a population pharmacokinetic analysis, steady-state necitumumab concentrations are predicted to be reached in approximately 100 days following IV infusion of necitumumab 800 mg on days 1 and 8 of each 21-day cycle.^[1] The elimination half-life of necitumumab in patients receiving the recommended dosage regimen is approximately 14 days.^[1]

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 advising patients to minimize sun exposure with protective clothing and use of sunscreen during necitumumab 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] Necessity of advising women of childbearing potential to use effective methods of contraception while receiving necitumumab and for 3 months after the last dose of the drug.^[1] If a patient becomes pregnant during therapy, apprise patient of potential hazard to the fetus.^[1]

Importance of advising women to avoid breast-feeding while receiving necitumumab therapy and for 3 months following the last dose of the drug.^[1]

Importance of informing patients of other important precautionary information.^[1] (See Cautions.)

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.

†Use is not currently included in the labeling approved by the US Food and Drug Administration.

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