Necitumumab (Portrazza, IMC-11F8, LY3012211) is a recombinant human lgG1 monoclonal antibody that binds to the human epidermal growth factor receptor (EGFR) and blocks the binding of EGFR to its ligands. It carries a black box warning for cardiopulmonary arrest and hypomagnesemia; patients receiving necitumumab should be closely monitored for hypomagnesemia, hypokalemia, and hypocalcemia; dermatologic toxicities are also common after treatment with necitumumab, and may become worse with sun exposure. Necitumumab is indicated for the first-line treatment of patients with metastatic squamous non-small cell lung cancer (NSCLC), in combination with gemcitabine and cisplatin, after demonstrating a significant improvement in overall survival (11.5 months vs. 9.9 months; p = 0.01) in patients treated with necitumumab plus gemcitabine and cisplatin compared with gemcitabine and cisplatin alone. Progression free survival was slightly improved (5.7 vs. 5.5 months; p = 0.02) in necitumumab-treated patients; however, the overall response rate was not significantly different (31% vs. 29%; p = 0.4). It is not indicated for the treatment of non-squamous NSCLC due to an increased incidence of serious and fatal toxicities as well as an increased incidence of death within 30 days of the last dose of study drug in a randomized clinical trial in patients who received necitumumab plus pemetrexed and cisplatin compared to patients treated with pemetrexed and cisplatin alone. Necitumumab was approved by the FDA in November 2015.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Emetic Risk
-Low
-Administer routine antiemetic prophylaxis prior to treatment.
Route-Specific Administration
Injectable Administration
-Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
-Necitumumab is a clear to slightly opalescent, colorless to pale-yellow solution. Discard the vial if the solution is cloudy, discolored, or contains extraneous particulate matter.
Infusion-Related Reactions:
-First grade 1 or 2 infusion-related reaction: Premedicate all subsequent infusions with diphenhydramine (or equivalent).
-Second grade 1 or 2 infusion-related reaction: Premedicate all subsequent infusions with diphenhydramine (or equivalent), acetaminophen (or equivalent), and dexamethasone (or equivalent).
Intravenous Administration
Preparation:
-Withdraw the required volume of drug and dilute with 0.9% Sodium Chloride injection in an IV infusion container to a final volume of 250 mL. Do not use solutions containing dextrose.
-Mix the diluted solution by gentle inversion. Do not shake.
-Do not dilute with other solutions or co-infuse with other electrolytes or medications.
-Discard partially used or empty vials of necitumumab.
-Storage: After preparation, store diluted solution either at room temperature (up to 25 degrees C or 77 degrees F) for no more than 4 hours, or under refrigeration (2 to 8 degrees C or 36 to 46 degrees F) for no more than 24 hours.
Administration:
-Administer via infusion pump over 60 minutes through a separate infusion line.
-Flush the line with 0.9% Sodium Chloride injection at the end of the infusion.
Hypomagnesemia occurred in 83% (grade 3 or 4, 20%) of patients with available laboratory results treated with necitumumab in combination with gemcitabine and cisplatin (n = 461 to 505) in a randomized, open-label clinical trial compared with 70% (grade 3 or 4, 7%) of those who received gemcitabine and cisplatin alone (n = 454 to 505). The median time to onset of hypomagnesemia and electrolyte abnormalities was 6 weeks (25th percentile, 4 weeks; 75th percentile, 9 weeks); resolution occurred in 43% of patients. Magnesium replacement therapy was required in 32% of patients in the necitumumab arm and 16% of those treated with gemcitabine and cisplatin alone. Additionally, hypokalemia (all grade, 28% vs. 18%; grade 3 or 4, 5% vs. 3%), hypocalcemia (all grade, 45% vs. 30%; grade 3 or 4, 6% vs. 2%), albumin-corrected hypocalcemia (all grade, 36% vs. 23%; grade 3 or 4, 4% vs. 2%), and hypophosphatemia (all grade, 31% vs. 23%; grade 3 or 4, 8% vs. 6%) occurred more often in the necitumumab arm than the control group.
In a randomized, open-label clinical trial, venous thromboembolism (VTE) occurred in 9% (grade 3 or 4, 5%) of patients receiving necitumumab plus gemcitabine and cisplatin (n = 538) compared with 5% (grade 3 or 4, 3%) of those treated with gemcitabine and cisplatin alone (n = 541), most commonly pulmonary embolism (all grade, 5% vs. 2%; grade 3 or 4, 4% vs. 2%) and deep-vein thrombosis (2%); fatal VTE occurred in 0.2% of patients in each arm. In addition to pulmonary embolism and deep-vein thrombosis, VTE also included thrombosis, mesenteric vein thrombosis, pulmonary artery thrombosis, venous thrombosis limb, axillary vein thrombosis, thrombophlebitis, thrombosis in device, vena cava thrombosis, venous thrombosis, subclavian vein thrombosis, superior vena cava syndrome, and superficial thrombophlebitis. Arterial thromboembolism was reported in 5% (>= grade 3, 4%) vs. 4% (>= grade 3, 2%) of patients, respectively, and was most commonly cerebral stroke and ischemia (2%) and myocardial infarction (1%).
Cardiac arrest, cardiopulmonary arrest, or sudden death occurred in 15 of 538 patients (3%) treated with necitumumab plus gemcitabine and cisplatin (n = 538) compared with 3 patients (0.6%) of those who received gemcitabine and cisplatin alone (n = 541) in a randomized, open-label clinical trial. Twelve of the fifteen patients died within 30 days of the last dose of necitumumab and had comorbid conditions such as a history of coronary artery disease (CAD) (n = 3), hypomagnesemia (n = 4), chronic obstructive pulmonary disease (COPD) (n = 7), and hypertension (n = 5); patients with significant CAD, myocardial infarction within 6 months, uncontrolled hypertension, and uncontrolled congestive heart failure (CHF) were excluded from the clinical trial.
Dermatologic toxicities occurred in 79% (grade 3 or 4, 8%) of patients treated with necitumumab plus gemcitabine and cisplatin in a randomized, open-label clinical trial. Skin toxicity usually developed within the first 2 weeks of therapy and resolved within 17 weeks after onset. Rash (unspecified) was reported in 44% (grade 3 or 4, 4%) of patients in the necitumumab arm (n = 538), compared to 6% (grade 3 or 4, 0.2%) of those who received gemcitabine and cisplatin alone (n = 541). Skin rash was the most common necitumumab-related toxicity leading to discontinuation of therapy, which occurred in 1% of patients. Additionally, acneiform rash (all grade, 15% vs. 0.6%; grade 3 or 4, 1% vs. 0%), acne vulgaris (all grade, 9% vs. 0.6%; grade 3 or 4, 0.4% vs. 0%), pruritus (all grade, 7% vs. 0.9%; grade 3 or 4, 0.2% vs. 0.2%), paronychia (all grade, 7% vs. 0.2%; grade 3 or 4, 0.4% vs. 0%), xerosis (all grade, 7% vs. 1%), and skin fissures (all grade, 5% vs. 0%; grade 3 or 4, 0.4% vs. 0%) occurred more often in the necitumumab arm; erythema and maculopapular rash were also reported.
In a randomized, open-label clinical trial, 29% (grade 3 or 4, 3%) of patients treated with necitumumab plus gemcitabine and cisplatin experienced vomiting (n = 538), compared with 25% (grade 3 or 4, 0.9%) of those who received gemcitabine and cisplatin alone (n = 541). Additionally, diarrhea (all grade, 16% vs. 11%; grade 3 or 4, 2% vs. 1%), stomatitis (all grade, 11% vs. 6%; grade 3 or 4, 1% vs. 0.6%), and weight loss (all grade, 13% vs. 6%; grade 3 or 4, 0.7% vs. 0.6%) occurred more often in the necitumumab arm. Dysphagia (3%) and oropharyngeal pain (1%) were also reported in necitumumab-treated patients.
In a randomized, open-label clinical trial, 10% (grade 3 or 4, 1%) of patients treated with necitumumab plus gemcitabine and cisplatin (n = 538) experienced hemoptysis, compared with 5% (grade 3 or 4, 0.9%) of those who received gemcitabine and cisplatin alone (n = 541).
In a randomized, open-label clinical trial, 11% of patients treated with necitumumab plus gemcitabine and cisplatin (n = 538) experienced headache, compared with 6% (grade 3 or 4, 0.4%) of those who received gemcitabine and cisplatin alone (n = 541).
In a randomized, open-label clinical trial, 7% (grade 3 or 4, 0.4%) of patients treated with necitumumab plus gemcitabine and cisplatin (n = 538) experienced conjunctivitis (including ocular irritation, blurred vision, bacterial conjunctivitis, xerophthalmia, reduced visual acuity, blepharitis, ocular hemorrhage, ocular infection, ocular pain, increased lacrimation, ocular or conjunctival hyperemia, Sjogren's syndrome, visual impairment, and ocular pruritus), compared with 2% of those who received gemcitabine and cisplatin alone (n = 541).
As with all therapeutic proteins, there is the potential for immunogenicity and antibody formation with necitumumab. Of 814 patients evaluated, treatment-emergent human anti-human antibody (HAHA) was detected in 4.1% of necitumumab-treated patients by an enzyme-linked immunosorbent assay (ELISA). In addition, neutralizing antibodies were detected in 1.4% of patients after exposure to necitumumab. No relationship was found between the presence of anti-necitumumab antibodies and the incidence of infusion-related reactions. In a randomized, open-label clinical trial (n = 1093), necitumumab exposure was lower in patients with post-treatment anti-necitumumab antibodies than in patients without detectable antibodies; the impact on efficacy and overall survival could not be assessed due to the limited number of patients. Immunogenicity data are highly dependent on the sensitivity and specificity of the test methods used. Results may be influenced by several factors, including sample handling, timing of sample collection, drug interference, concomitant medication and the underlying disease. Comparison of the incidence of antibodies to necitumumab with the incidence of antibodies to other products may be misleading.
Cardiac arrest, cardiopulmonary arrest, and/or sudden death have occurred in patients treated with necitumumab in combination with gemcitabine and cisplatin. Closely monitor serum electrolytes prior to each dose of necitumumab and for 8 weeks after the last dose; aggressively correct any electrolyte imbalance that is detected such as hypomagnesemia, hypokalemia, and hypocalcemia. Do not administer necitumumab if grade 3 or 4 electrolyte abnormalities are present until they have resolved to grade 2 or less. In a randomized, open-label clinical trial, 12 of the 15 necitumumab-treated patients (n = 538) who experienced cardiopulmonary arrest or sudden death had comorbid conditions such as a history of coronary artery disease (CAD), hypomagnesemia, chronic obstructive pulmonary disease (COPD), and hypertension. Patients with significant CAD, myocardial infarction within 6 months, uncontrolled hypertension, and uncontrolled congestive heart failure (CHF) were excluded from this trial. Use necitumumab with caution in patients with a history of CAD, CHF, or cardiac arrhythmias, as the risk of cardiac arrest or sudden death is not known.
Venous and arterial thromboembolism (VTE and ATE), including fatalities, have been reported when necitumumab was used in combination with gemcitabine and cisplatin. In an exploratory analysis of a randomized, open-label clinical trial, the relative risk of VTE or ATE was approximately 3-fold higher in patients with a history of thromboembolic disease; there was also a higher incidence (>= 3%) of VTE, including pulmonary embolism, in geriatric patients (age >= 70 years). Use necitumumab with caution in patients with pre-existing thromboembolic disease or geriatric patients. Discontinue necitumumab in patients with serious or life threatening VTE or ATE.
Dermatologic toxicities, including serious rash, were commonly reported in patients treated with necitumumab in combination with gemcitabine and cisplatin in a randomized, open-label clinical trial. Sunlight (UV) exposure should be limited; a dose modification or discontinuation of therapy may be necessary if skin toxicities develop. The typical time to onset was within the first 2 weeks of therapy, with resolution occurring 17 weeks after onset.
Infusion-related reactions have been reported in patients treated with necitumumab; most occurred after the first or second administration. Monitor patients for signs and symptoms of infusion-related reactions during and after necitumumab infusions. If a grade 1 or higher infusion-related reaction occurs, slowing or stopping the infusion may be necessary; premedication is necessary prior to administration of subsequent doses of necitumumab. Discontinue necitumumab for serious or life-threatening reactions.
Of 814 patients evaluated, treatment-emergent human anti-human antibody (HAHA) was detected in 4.1% of patients treated with necitumumab. In addition, neutralizing antibodies were detected in 1.4% of patients after exposure to necitumumab. No relationship was found between the presence of anti-necitumumab antibodies and the incidence of infusion-related reactions. In a randomized, open-label clinical trial (n = 1093), necitumumab exposure was lower in patients with post-treatment anti-necitumumab antibodies than in patients without detectable antibodies; the impact on efficacy and overall survival could not be assessed due to the limited number of patients. Immunogenicity data are highly dependent on the sensitivity and specificity of the test methods used. Results may be influenced by several factors, including sample handling, timing of sample collection, drug interference, concomitant medication and the underlying disease. Comparison of the incidence of antibodies to necitumumab with the incidence of antibodies to other products may be misleading.
Although there are no adequate and well-controlled studies in pregnant women, necitumumab can cause fetal harm when administered during pregnancy based on its mechanism of action and animal data. Disruption or depletion of EGFR in animal models causes impairment of embryofetal development, including adverse effects on placental, lung, cardiac, skin, and neural development. In mice, EGFR is critically important in reproductive and developmental processes including blastocyst implantation, placental development, and embryo-fetal/post-natal survival and development; EGFR inhibition can prevent implantation, cause embryo-fetal loss during various stages of gestation, and can cause developmental anomalies and early death in surviving fetuses. Human IgG1 is known to cross the placenta; therefore, necitumumab has the potential to cross the placenta and be transmitted from mother to fetus. In monkeys, administration of a chimeric anti-EGFR antibody that binds to an epitope overlapping that of necitumumab during organogenesis resulted in detectable exposure in the amniotic fluid and in the serum of embryos from treated dams. While no fetal malformations or other clear teratogenic effects occurred, there was an increased incidence of embryo-lethality and abortions.
Counsel patients about the reproductive risk and contraception requirements during necitumumab treatment. Necitumumab can cause fetal harm if taken by the mother during pregnancy. Females should avoid pregnancy and use effective contraception during and for at least 3 months after the final dose of necitumumab. It is prudent that females of reproductive potential undergo pregnancy testing prior to initiation of therapy. Women who become pregnant while receiving necitumumab should be apprised of the potential hazard to the fetus. Fertility studies have not been performed with necitumumab.
It is not known whether necitumumab is present in human milk. Many drugs are excreted in human milk including antibodies. Due to the potential for serious adverse reactions in nursing infants from necitumumab, advise women to discontinue breast-feeding during treatment and for 3 months after the last dose.
For the first-line treatment of metastatic squamous non-small cell lung cancer (NSCLC), in combination with gemcitabine and cisplatin:
NOTE: The FDA has designated necitumumab as an orphan drug for the treatment of squamous NSCLC.
Intravenous dosage:
Adults: 800 mg IV over 60 minutes on days 1 and 8, followed by gemcitabine (1,250 mg/m2 IV on days 1 and 8) and cisplatin (75 mg/m2 IV on day 1), every 3 weeks for 6 cycles. After completion of 6 cycles of chemotherapy, continue necitumumab 800 mg IV over 60 minutes on days 1 and 8, every 3 weeks until disease progression or unacceptable toxicity. Administer appropriate hydration prior to cisplatin administration and maintain hydration and adequate urinary output for 24 hours after cisplatin administration. Treatment with necitumumab, gemcitabine, and cisplatin significantly improved median overall survival (OS) in patients with previously untreated metastatic squamous NSCLC compared with gemcitabine and cisplatin without necitumumab (11.5 months vs. 9.9 months) in a randomized, open-label trial. Investigator-assessed progression-free survival (PFS) was also significantly improved in the necitumumab arm (5.7 months vs. 5.5 months); the overall response rate was 31% versus 29%, respectively. Necitumumab is not effective in the treatment of non-squamous NSCLC. Another multicenter, randomized, open-label clinical trial was closed early due to an increased incidence of death due to any cause and thromboembolic events in patients who received necitumumab plus pemetrexed and cisplatin compared to pemetrexed and cisplatin alone; more serious (51% vs. 41%) and fatal (16% vs. 10%) toxicities occurred in the necitumumab arm, as well as an increased incidence of cardiopulmonary arrest/sudden death within 30 days of the last study drug (3.3% vs. 1.3%). In this study, neither OS, PFS, nor ORR were significantly improved with the addition of necitumumab to pemetrexed and cisplatin.
Therapeutic Drug Monitoring:
Dosage Adjustments for Treatment-Related Toxicity :
Infusion-Related Reactions (IRR)
-Grade 1 IRR: Reduce the rate of necitumumab infusion by 50%. For the first grade 1 IRR, premedicate all subsequent infusions with diphenhydramine (or equivalent). For the second grade 1 IRR, premedicate all subsequent infusions with diphenhydramine (or equivalent), acetaminophen (or equivalent), and dexamethasone (or equivalent).
-Grade 2 IRR: Hold necitumumab infusion. When signs and symptoms resolve to grade 1 or less, resume the necitumumab infusion at 50% reduced rate for all subsequent infusions. For the first grade 2 IRR, additionally premedicate all subsequent infusions with diphenhydramine (or equivalent). For the second grade 2 IRR, premedicate all subsequent infusions with diphenhydramine (or equivalent), acetaminophen (or equivalent), and dexamethasone (or equivalent).
-Grade 3 or 4 IRR: Permanently discontinue necitumumab.
Dermatologic Toxicity
-Grade 3 rash or acneiform rash (not skin induration/fibrosis): Hold necitumumab. If symptoms resolve to grade 2 or less within 6 weeks, resume necitumumab at a reduced dose of 400 mg for at least 1 treatment cycle. If symptoms do not worsen, consider increasing the dose to 600 mg and 800 mg in subsequent cycles. Permanently discontinue necitumumab if the rash does not improve to grade 2 or less within 6 weeks or if the reaction worsens or becomes intolerable at a dose of 400 mg.
-Grade 3 skin induration/fibrosis or grade 4 dermatologic toxicity: Permanently discontinue necitumumab.
Electrolyte Abnormalities
-Grade 3 or 4 electrolyte abnormalities: Hold necitumumab and replete electrolytes as appropriate. Resume necitumumab therapy when electrolyte abnormalities have improved to grade 2 or less.
Thromboembolic Events
-Serious or life-threatening venous or arterial thromboembolism: Discontinue necitumumab therapy.
Maximum Dosage Limits:
-Adults
800 mg IV on day 1 and 8.
-Geriatric
800 mg IV on day 1 and 8.
-Adolescents
Safety and efficacy have not been established.
-Children
Safety and efficacy have not been established.
-Infants
Safety and efficacy have not been established.
-Neonates
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
Formal studies have not evaluated the effect of hepatic impairment on necitumumab exposure, therefore specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed. Patients with severe hepatic impairment were not enrolled in clinical trials.
Patients with Renal Impairment Dosing
Formal studies have not evaluated the effect of renal impairment on necitumumab exposure, therefore specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.
*non-FDA-approved indication
Cholera Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the live cholera vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to cholera bacteria after receiving the vaccine.
Dengue Tetravalent Vaccine, Live: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the dengue virus vaccine. When feasible, administer indicated vaccines at least 2 weeks prior to initiating immunosuppressant medications. If vaccine administration is necessary, consider revaccination following restoration of immune competence. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure after receiving the vaccine.
SARS-CoV-2 (COVID-19) vaccines: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) Adenovirus Vector Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) mRNA Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) Recombinant Spike Protein Nanoparticle Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
Tuberculin Purified Protein Derivative, PPD: (Moderate) Immunosuppressives may decrease the immunological response to tuberculin purified protein derivative, PPD. This suppressed reactivity can persist for up to 6 weeks after treatment discontinuation. Consider deferring the skin test until completion of the immunosuppressive therapy.
Necitumumab is an anti-EGFR recombinant human monoclonal antibody of the IgG1 kappa isotope that specifically binds to and blocks the ligand binding site of the human EGFR. Expression and activation of EGFR has been correlated with malignant progression, angiogenesis, and inhibition of apoptosis. In vitro, necitumumab induces EGFR internalization and degradation, leading to antibody-dependent cellular cytotoxicity (ADCC) in EGFR-expressing cells. Compared with gemcitabine and cisplatin alone, the addition of necitumumab increased antitumor activity in vivo in studies using xenograft models of human cancer, including non-small cell lung cancer (NSCLC), in implanted mice.
Necitumumab is administered intravenously, and exhibits dose-dependent pharmacokinetics. After administration of necitumumab 800 mg on days 1 and 8 of each 21 day cycle, the estimated mean total systemic clearance at steady-state is 14.1 mL/h (CV, 39%), the steady-state volume of distribution (Vd) is 7 L (CV, 31%), and the elimination half-life is approximately 14 days. The predicted time to reach steady state is approximately 100 days.
-Special Populations
Hepatic Impairment
Based on a population pharmacokinetic analysis, mild to moderate hepatic impairment (ALT 2 to 615 units/L, AST 1.2 to 619 units/L, or total bilirubin 0.1 to 106 micromol/L) does not influence necitumumab exposure. Patients with severe hepatic impairment were enrolled in necitumumab clinical trials.
Renal Impairment
Based on a population pharmacokinetic analysis, renal function (CrCL 11 to 250 mL/min) does not influence necitumumab exposure.
Geriatric
Based on a population pharmacokinetic analysis, age does not effect the systemic exposure of necitumumab.
Gender Differences
Based on a population pharmacokinetic analysis, gender does not effect the systemic exposure of necitumumab.
Ethnic Differences
Based on a population pharmacokinetic analysis, ethnicity does not effect the systemic exposure of necitumumab.
Obesity
Body weight is identified as a covariate in a population pharmacokinetic analysis; however, weight-based dosing is not expected to significantly decrease the variability in necitumumab exposure. Dose adjustments based on body weight are not necessary.
Other
Anti-necitumumab Antibodies:
In a randomized, open-label clinical trial (n = 1093), necitumumab clearance was 26% higher and steady-state concentrations 34% lower in patients who tested positive for anti-necitumumab antibodies than in patients who tested negative for treatment-emergent antibodies.