Cetuximab is a recombinant, human/mouse chimeric monoclonal antibody that binds specifically to the extracellular domain of the human epidermal growth factor receptor (EGFR), mediating antibody-dependent cellular cytotoxicity (ADCC) against certain human tumor types. It is indicated for the treatment of advanced head and neck cancer in combination with radiation therapy or platinum-based chemotherapy, or as monotherapy following progression after platinum-based therapy; for the treatment of advanced KRAS wild-type, EGFR-positive colorectal cancer (CRC) in combination with FOLFIRI or irinotecan, or as monotherapy in patients who have failed oxaliplatin- and irinotecan-based chemotherapy or are intolerant to irinotecan; and for the treatment of BRAF V600E mutation-positive metastatic CRC in combination with encorafenib. In vitro assays and in vivo animal studies have shown that cetuximab inhibits the growth and survival of tumor cells that express EGFR; no anti-tumor effects were observed in human tumor xenografts lacking EGFR expression. Induction of EGFR-mediated MAPK pathway activation has been identified as a mechanism of resistance to BRAF inhibitors in BRAF-mutant CRC; combinations of a BRAF inhibitor and EGFR inhibitors have overcome this resistance in nonclinical models. Confirmation of EGFR and Ras status, as well as BRAF V600E mutation status if applicable, is required prior to treatment for CRC; because EGFR expression has been detected in nearly all SCCHN tumor specimens, patients are not required to have immunohistochemical evidence of EGFR tumor expression prior to treatment. Treatment with cetuximab can result in severe infusion-related reactions as well as cardiopulmonary arrest and sudden death. Closely monitor serum electrolytes, including serum magnesium, potassium, and calcium, during and after treatment with cetuximab. Mucocutaneous adverse reactions and dermatologic toxicities are also common; patients should be instructed to limit sun exposure.
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.
Intravenous Administration
-Only administer in a hospital or clinic setting with full resuscitation equipment and under the supervision of a physician experienced with chemotherapy administration.
-Premedicate 30 to 60 minutes prior to the first dose or subsequent doses with an IV H1 antagonist (e.g., diphenhydramine 50 mg) as necessary.
-Do not shake or further dilute vial. Do not mix with other medications.
-Administer only as an IV infusion via a controlled rate IV infusion pump or syringe pump with a low-protein binding 0.22 micrometer in-line filter; do not administer as a bolus injection or as an intravenous push.
-Infuse 400 mg/m2 and 500 mg/m2 doses over 2 hours (maximum rate, 10 mg/minute).
-Infuse 250 mg/m2 doses over 1 hour (maximum rate, 10 mg/minute).
-Following completion of infusion, monitor patients for at least one hour. Appropriate medical resources for the treatment of severe infusion reactions should be available during cetuximab infusion (e.g., epinephrine, corticosteroids, IV antihistamines, bronchodilators, and oxygen). For individuals who experience infusion-related reactions, a prolonged observation period may be required to confirm resolution.
Cardiac arrest, respiratory arrest, and/or sudden death occurred in 2% of patients treated with cetuximab plus radiation therapy in a randomized clinical trial (n = 420). Three patients with prior history of coronary artery disease died at home with myocardial infarction as the presumed cause of death at 27, 32, and 43 days after the last dose of cetuximab; one of these patients had arrhythmia and one had congestive heart failure. One patient with no prior history of coronary artery disease died one day after the last dose of cetuximab. Fatal cardiac disorders and/or sudden death occurred in 3% of patients with advanced squamous cell head and neck cancer treated with a cetuximab product in combination with platinum-based chemotherapy and 5-FU (n = 219) in another clinical trial. Acute myocardial infarction, myocardial ischemia, angina pectoris, prinzmetal angina, and heart failure have all been reported with cetuximab therapy in association with infusion reactions.
Pulmonary embolism was reported in 4.4% of patients with KRAS wild-type, EGFR-positive, metastatic colorectal cancer treated with cetuximab in combination with FOLFIRI compared with 3.4% of those who received FOLFIRI alone in a randomized clinical trial.
Interstitial lung disease (ILD)/pneumonitis, including 1 fatality, occurred in less than 0.5% of patients receiving cetuximab in clinical trials (n = 1,570). Interrupt cetuximab for acute onset or worsening of pulmonary symptoms and permanently discontinue cetuximab therapy if ILD is confirmed. Symptoms including dyspnea (49% vs. 44%; grade 3 or 4, 16% vs. 13%) and cough (30% vs. 19%; grade 3 or 4, 2% vs. 2%) were also reported more frequently in cetuximab-treated patients with KRAS mutation negative, EGFR-expressing, metastatic colorectal carcinoma (n = 118) compared with those receiving best supportive care (n = 124) in an open-label clinical trial.
Fever was reported in 25% to 29% (grade 3 or 4, 1% to 3%) of patients treated with cetuximab monotherapy or in combination with radiation therapy in clinical trials; it was also reported as one of several components of hypersensitivity reactions associated with cetuximab infusions. Fever occurred with a similar frequency in patients treated with cetuximab plus platinum-based chemotherapy in clinical trials (22% to 26%; grade 3 or 4, 1% or less). The incidence of fever was similar in patients with metastatic colorectal cancer who received cetuximab in combination with encorafenib versus irinotecan or FOLFIRI (17% vs. 15%; grade 3 or 4, 1% vs. 1%).
Serious and fatal infusion-related reactions, including serious hypersensitivity reactions or anaphylaxis, requiring medical intervention and immediate, permanent discontinuation of cetuximab included rapid onset of bronchospasm, stridor, hoarseness, hypotension, anaphylactic shock, loss of consciousness, myocardial infarction, and/or cardiac arrest. Infusion reactions occurred in 8.4% (grade 3 or 4, 2.2%) of patients treated with cetuximab across clinical trials (n = 1,373); approximately 90% of severe infusion reactions occurred with the first infusion despite premedication with antihistamines. The infusion rate may be decreased for mild to moderate reactions; discontinue cetuximab for serious infusion reactions. In individual clinical trials, chills/rigors were reported in 16% (grade 3 or 4, 1% or less) and infusion reactions in 10% to 18% (grade 3 or 4, 2% to 3%) of patients treated with cetuximab. In these trials, the following terms were additionally included as infusion reactions: allergic reaction, anaphylactoid reactions, angioedema, autonomic seizures, bronchospasm, chills (on the first day of dosing), clonus, convulsion, diaphoresis, dyspnea (on the first day of dosing), epilepsy, fever (on the first day of dosing), flushing, hypersensitivity, abnormal/decreased/increased blood pressure, hypertension, hypertensive crisis, hypertensive emergency, hypotension, rigors, shock, sinus tachycardia, syncope, tremor, and urticaria.
Infection occurred in 13% to 35% of patients treated with cetuximab across clinical trials, with sepsis occurring in 1% to 4% of patients. In patients with metastatic colorectal cancer, non-neutropenic infection occurred in 38% (grade 3 or 4, 11%) of patients treated with cetuximab monotherapy (n = 118) compared with 19% (grade 3 or 4, 5%) of those treated with best supportive care (n = 124). In a randomized clinical trial of patients with head and neck cancer who received radiation therapy with (n = 208) or without (n = 212) cetuximab, infection was reported in 13% (grade 3 or 4, 1%) compared with 9% (grade 3 or 4, 1%) of patients, while pharyngitis was separately reported at 26% (grade 3 or 4, 3%) versus 19% (grade 3 or 4, 4%) of patients, respectively. Infections were also more common in patients receiving cetuximab plus platinum-based chemotherapy (n = 219) compared with chemotherapy alone (n = 215) (44% vs. 27%; grade 3 or 4, 11% vs. 8%) in a randomized clinical trial. Paronychia was reported in one trial of patients receiving FOLFIRI with (n = 317) or without (n = 350) cetuximab (20% vs. less than 1%; grade 3 or 4, 4% vs. 0%). Dermatologic toxicities have also resulted in infectious sequelae in clinical trials, including S. aureus sepsis, abscess formation, and cellulitis. Aseptic meningitis was reported in postmarketing experience with cetuximab.
Life-threatening and fatal bullous mucocutaneous disease with blisters, skin erosion, and skin sloughing has been observed in postmarketing reports of patients treated with cetuximab. It was not able to be determined whether the reactions were related to EGFR inhibition or to idiosyncratic immune-related effects (e.g., Stevens-Johnson syndrome or toxic epidermal necrolysis). Dermatologic toxicities including skin fissures, cheilitis, and hypertrichosis also occurred. Acneiform rash is very common with cetuximab therapy, occurring in 82% (grade 3 or 4, 9.7%) of patients treated with cetuximab across clinical trials (n = 1,373) acne, exfoliative dermatitis, erythema, maculopapular rash, pustular rash, butterfly rash, drug reaction with eosinophilia and systemic symptoms (DRESS), folliculitis, genital rash, morbilliform rash, vesicular rash, rubelliform rash, scarlatiniform rash, skin hyperpigmentation, skin plaque, telangiectasia, and xerosis. It usually develops within the first 2 weeks of therapy and has lasted more than 28 days after stopping cetuximab in most patients. The incidence of acneiform rash was lower in cetuximab-treated patients receiving concomitant encorafenib compared with those receiving concomitant irinotecan or FOLFIRI. Rash/desquamation (not reported as acneiform) occurred in 95% (grade 3 or 4, 16%) of patients receiving cetuximab monotherapy in one trial. In combination with chemotherapy and reported separately from "acneiform rash", rash occurred in 28% to 44% (grade 3 or 4, 5% to 9%), acne vulgaris in 14% to 22% (grade 3 or 4, 2%), and acneiform dermatitis in 15% to 26% (grade 3 or 4, 2% to 5%) of cetuximab-treated patients; additional dermatologic adverse reactions reported more often in cetuximab-treated patients compared with control arms in clinical trials included xerosis (14% to 57%) and pruritus (14% to 47%; grade 3 or 4, 2% or less). Mild rash (26%), xerosis (13%), pruritus (14%), and melanocytic nevus (14%) occurred in patients treated with cetuximab plus encorafenib. Alopecia occurred in 12% of patients who received cetuximab plus platinum-based chemotherapy, which was similar to chemotherapy alone. Palmar-plantar erythrodysesthesia (hand and foot syndrome) (19% vs. 4%; grade 3 or 4, 4% vs. less than 1%) and skin fissures (19% vs. 1%); grade 3 or 4, 2% vs. 0%) were more common in patients treated with cetuximab plus FOLFIRI compared with FOLFIRI alone. Nail changes occurred in 31% of patients treated with cetuximab monotherapy compared with 4% of those receiving best supportive care; other dermatology reactions occurred in 35% versus 7% (grade 3 or 4, 0% vs. 2%) of patients, respectively. And finally, radiation dermatitis occurred in 86% (grade 3 or 4, 23%) of patients treated with cetuximab plus radiation compared with 90% (grade 3 or 4, 18%) of those treated with radiation alone; application site reactions occurred in 18% versus 12% (grade 3 or 4, 0% vs. 1%) of patients, respectively. Late radiation toxicities to subcutaneous tissue (49% vs. 45%) and skin (42% vs. 33%) were also more common in the cetuximab arm.
In general, the addition of cetuximab to a treatment regimen slightly increases the incidence of gastrointestinal adverse reactions. Nausea (64% vs. 50%; grade 3 or 4, 6% vs. 6%) and vomiting (40% vs. 26%; grade 3 or 4, 5% vs. 5%) were more common in patients with metastatic colorectal cancer (mCRC) treated with cetuximab monotherapy compared to those receiving best supportive care in a randomized clinical trial. In patients with locally advanced squamous cell cancer of the head and neck, nausea (49% vs. 37%; grade 3 or 4, 2% vs. 2%), vomiting (29% vs. 23%; grade 3 or 4, 2% vs. 4%), and dyspepsia (14% vs. 9%; grade 3 or 4, 0% vs. 1%) are also more common in patients treated with cetuximab plus radiation compared with radiation therapy alone. Nausea occurred in 54% of head and neck cancer patients treated with cetuximab plus platinum-based chemotherapy compared with 47% of those treated with platinum-based chemotherapy alone (grade 3 or 4, 4% vs. 4%). Nausea occurred in 41% to 55% (grade 3 or 4, 1% or less), vomiting in 29% or less (grade 3 or 4, 3% or less), and dyspepsia in 16% or less of patients with colorectal cancer treated with cetuximab plus FOLFIRI. The incidence of nausea (34% vs. 41%; grade 3 or 4, 1% vs. 1%) and vomiting (21% vs. 29%; grade 3 or 4, 1% vs. 3%) was lower in mCRC patients treated with cetuximab in combination with encorafenib versus irinotecan or FOLFIRI.
Renal failure (unspecified) was reported in 1% of patients with colorectal cancer treated with cetuximab in clinical trials. Dehydration, which could potentially lead to or exacerbate renal failure, was reported in 13% to 25% (grade 3 or 4, 5% to 6%) of patients receiving cetuximab monotherapy (n = 118) or in combination with radiation therapy (n = 208).
Anti-cetuximab binding antibody formation occurred in less than 5% of cetuximab-treated patients with at least 1 post-baseline blood sample (4 weeks or more after first cetuximab infusion). Anti-cetuximab IgE antibodies were present before treatment in 68% of patients who had previously received cetuximab and subsequently had a hypersensitivity reaction (n = 25), whereas only 2% of patients without a hypersensitivity reaction had anti-cetuximab IgE present (n = 51). The IgE antibodies were specific for an oligosaccharide, galactose--1,3-galactose, which is present on the Fab portion of the cetuximab heavy chain; these antibodies have also been detected in patients who never received cetuximab.
Hypomagnesemia occurred in 55% (grade 3 or 4, 6% to 17%) of patients receiving cetuximab in 3 clinical trials. The mechanism may be impaired magnesium reabsorption due to blocking of the epidermal growth factor receptor (EGFR) by cetuximab, which is abundantly expressed in the kidney. A significant amount of filtered magnesium is reabsorbed at the ascending limb of the loop of Henle. When administered in combination with platinum chemotherapy, the incidence of hypomagnesemia (11% vs. 5%; grade 3 or 4, 5% vs. 1%) as well as hypocalcemia (12% vs. 5%; grade 3 or 4, 4% vs. 1%) and hypokalemia (12% vs. 7%; grade 3 or 4, 7% vs. 5%) was higher in those who received cetuximab compared with those who received chemotherapy alone. In a subgroup analysis, hypomagnesemia occurred in 14% (grade 3 or 4, 7%) of patients receiving cetuximab plus cisplatin/fluorouracil and in 4% of patients receiving cetuximab plus carboplatin/fluorouracil. Hypomagnesemia (19% vs. 22%; grade 3 or 4, 0% vs. 1%) and hyponatremia (11% vs. 13%; grade 3 or 4, 2% vs. 2%) occurred with a similar frequency in patients who received cetuximab plus encorafenib versus cetuximab plus irinotecan or FOLFIRI; hypokalemia was more common in the chemotherapy arm (12% vs. 32%; grade 3 or 4, 3% vs. 5%). Electrolyte abnormalities can develop within days to months after the initiation of cetuximab. Monitor patients for hypomagnesemia, hypocalcemia, and hypokalemia during and for at least 8 weeks after the completion of cetuximab. Replete electrolytes as necessary.
Headache was reported in 38% (grade 3 or 4, 2%) of patients with metastatic colorectal cancer (mCRC) treated with cetuximab compared with 11% (grade 3 or 4, 0%) of those who received best supportive care (BSC) in a randomized clinical trial. In other trials, headache was also more common in mCRC patients receiving cetuximab plus encorafenib compared with cetuximab plus irinotecan or FOLFIRI (20% vs. 3%) and in head and neck cancer patients receiving cetuximab plus radiation compared with radiation therapy alone (19% vs. 8%; grade 3 or 4, less than 1% vs. less than 1%). Peripheral neuropathy occurred in 12% (grade 3 or 4, 1%) of mCRC patients receiving cetuximab plus encorafenib compared with 6% of those who received cetuximab plus chemotherapy. Insomnia occurred in 27% of patients receiving cetuximab monotherapy and in 13% of patients treated with cetuximab plus encorafenib. Additional neurologic adverse reactions that occurred with cetuximab monotherapy included sensory neuropathy (45%; grade 3 or 4, 1%), confusion (18%; grade 3 or 4, 6%), anxiety (14%; grade 3 or 4, 1%), and depression (14%).
Elevated hepatic enzymes were reported more often in patients with advanced head and neck cancer treated with cetuximab in combination with radiation therapy compared with those treated with radiation therapy alone, including increased ALT (43% vs. 21%; grade 3 or 4, 2% vs. 1%), increased AST (38% vs. 24%; grade 3 or 4, 1% vs. 1%), and increased alkaline phosphatase (33% vs. 24%; grade 3 or 4, less than 1% vs. 0%). Increased ALT (17% vs. 29%; grade 3 or 4, 0% vs. 3%), increased AST (15% vs. 22%; grade 3 or 4, 1% vs. 2%), and increased alkaline phosphatase (18% vs. 30%; grade 3 or 4, 4% vs. 7%) were less common in patients with metastatic colorectal cancer who received cetuximab plus encorafenib compared with those who received cetuximab plus irinotecan or FOLFIRI in another clinical trial.
Bone pain (15%; grade 3 or 4, 4%) and arthralgia (14%; grade 3 or 4, 3%) occurred more often in patients with metastatic colorectal cancer who received cetuximab plus best supportive care (BSC) compared with patients who received BSC alone in a randomized clinical trial. In another trial, arthralgia (27% vs. 3%; grade 3 or 4, 4% vs. 0%), myopathy (15% vs. 4%; grade 3 or 4, 0% vs. 1%), and extremity pain (10% vs. 1%) were also more common in mCRC patients who received cetuximab plus encorafenib compared to cetuximab plus irinotecan or FOLFIRI. Other types of pain were reported in 59% (grade 3 or 4, 18%) of patients in the cetuximab arm compared with 37% (grade 3 or 4, 10%) of those receiving only BSC.
Fatigue was reported in 91% (grade 3 or 4, 31%) of patients with metastatic colorectal cancer (mCRC) treated with cetuximab monotherapy compared with 79% (grade 3 or 4, 29%) of those receiving best supportive care in a randomized clinical trial. The incidence of fatigue was similar in mCRC patients treated with cetuximab in combination with encorafenib versus irinotecan or FOLFIRI (51% vs. 50%; grade 3 or 4, 7% vs. 8%). Asthenia was also more common in patients with advanced head and neck cancer when cetuximab was added to radiation therapy compared with radiation therapy alone (56% vs. 49%; grade 3 or 4, 4% vs. 5%). Asthenia/malaise was among the most frequently reported adverse reactions in patients treated with cetuximab plus irinotecan in clinical trials (73%; grade 3 or 4, 16%).
In one clinical trial, patients with metastatic colorectal cancer (mCRC) who received cetuximab in combination with FOLFIRI reported neutropenia more often than those treated with FOLFIRI alone (49% vs. 42%; grade 3 or 4, 31% vs. 24%). Additionally, grade 3 or 4 leukopenia was reported in 17% of patients treated with cetuximab plus irinotecan. In another clinical trial, anemia (34% vs. 48%; grade 3 or 4, 4% vs. 5%) and lymphopenia (24% vs. 35%; grade 3 or 4, 7% vs. 5%).
Blepharitis, conjunctivitis, keratitis, and ulcerative keratitis with decreased visual acuity (visual impairment) have occurred in patients treated with cetuximab in clinical trials. Conjunctivitis was reported in 10% to 18% of patients treated with cetuximab plus chemotherapy (platinum based chemotherapy or FOLFIRI; n = 536) in two separate clinical trials (grade 3 or 4, less than 1%), compared with 3% or less of patients in the chemotherapy arms (n = 565).
Diarrhea occurred in 42% (grade 3 or 4, 2%) of patients with metastatic colorectal cancer (mCRC) treated with cetuximab monotherapy compared with 23% (grade 3 or 4, 2%) of those receiving best supportive care. Constipation was also more common in the cetuximab arm (53% vs. 38%; grade 3 or 4, 3% vs. 3%). In patients with squamous cell cancer of the head and neck (SCCHN), diarrhea occurred in 19% of patients receiving cetuximab plus radiation compared with 13% of those receiving radiation alone (grade 3 or 4, 2% vs. 1%). In combination with chemotherapy, the addition of cetuximab causes a generally modest increase in the incidence of diarrhea, including in patients with SCCHN receiving platinum-based chemotherapy (26% vs. 16%; grade 3 or 4, 5% vs. 1%) and in patients with mCRC receiving FOLFIRI or irinotecan (48% to 72% vs. 60%; grade 3 or 4, 10% to 22% vs. 10%). The incidence of diarrhea was lower in mCRC patients treated with cetuximab in combination with encorafenib versus irinotecan or FOLFIRI (33% vs. 48%; grade 3 or 4, 2% vs. 10%); the incidence of abdominal pain (30% vs. 32%; grade 3 or 4, 4% vs. 5%) and constipation (15% vs. 18%; grade 3 or 4, 0% vs. 1%) were similar.
Weight loss occurred in 84% of patients with squamous cell cancer of the head and neck (SCCHN) treated with cetuximab plus radiation compared with 72% of those receiving radiation alone in a randomized clinical trial (grade 3 or 4, 11% vs. 7%). Decreased appetite or anorexia has been reported with a slightly higher frequency in patients treated with cetuximab added to chemotherapy compared with chemotherapy alone in several clinical trials, including in patients with SCCHN receiving platinum-based chemotherapy (25% vs. 14%; grade 3 or 4, 5% vs. 1%) and in patients with metastatic colorectal cancer (mCRC) receiving irinotecan or FOLFIRI (27% to 30% vs. 23%; grade 3 or 4, 3% vs. 2%). The incidence of decreased appetite was similar in mCRC patients treated with cetuximab in combination with encorafenib versus irinotecan or FOLFIRI (27% vs. 27%; grade 3 or 4, 2% vs. 3%) in another trial.
Stomatitis occurred in 32% of patients with metastatic colorectal cancer (mCRC) treated with cetuximab monotherapy compared with 10% of those receiving best supportive care in a randomized clinical trial (grade 3 or 4, 1% vs. 0%). Xerostomia was reported in 12% versus 6% of patients, respectively. The overall incidence of late radiation toxicities of any grade was also higher in patients with squamous cell cancer of the head and neck receiving cetuximab plus radiation therapy compared with radiation therapy alone, with sites including salivary glands (65% vs. 56%), larynx (52% vs. 36%), subcutaneous tissue (49% vs. 45%), mucous membrane (48% vs. 39%), esophagus (44% vs. 35%), and skin (42% vs. 33%); the incidence of grade 3 or 4 late radiation toxicities was similar between treatment arms. Stomatitis occurred in 31% of patients with mCRC receiving cetuximab plus FOLFIRI compared with 19% of those receiving FOLFIRI alone (grade 3 or 4, 3% vs. 1%). Mucosal inflammation has also been reported in postmarketing experience with cetuximab.
Dysgeusia occurred in 10% of patients with metastatic colorectal cancer treated with cetuximab monotherapy compared with 5% of those receiving best supportive care in a randomized clinical trial.
Bleeding/hemorrhage occurred in 19% (grade 3 or 4, 2%) of patients with metastatic colorectal cancer treated with cetuximab plus encorafenib compared with 9% of those who received cetuximab plus irinotecan or FOLFIRI in a randomized clinical trial; one patient in the encorafenib arm died. Prolonged bleeding time also occurred, with increased activated partial thromboplastin time (aPTT) reported in 13% (grade 3 or 4, 1%) of patients in the encorafenib arm compared with 7% (grade 3 or 4, 1%) of those in the chemotherapy arm.
Pancreatitis occurred in less than 10% of patients with metastatic colorectal cancer treated with cetuximab plus encorafenib in a randomized clinical trial.
Cetuximab should be used with caution in patients with known murine protein hypersensitivity or hypersensitivity to any component of the product. Severe and fatal infusion-related reactions requiring medical intervention and immediate, permanent discontinuation of cetuximab therapy may occur and are characterized by the rapid onset of airway obstruction (e.g., acute bronchospasm, stridor, hoarseness), hypotension, and shock. The risk of anaphylactic reactions may be increased in patients with a history of tick bites, red meat hypersensitivity/allergy, or in the presence of IgE antibodies directed against galactose-alpha-1, 3-galactose (alpha-gal syndrome). Consider testing patients for alpha-gal IgE antibodies prior to initiating cetuximab therapy; negative results do not rule out the risk of severe infusion reactions. Monitor patients for at least 1 hour after administration of cetuximab in a setting with resuscitation equipment and other agents necessary to treat anaphylaxis (e.g., epinephrine, corticosteroids, IV antihistamines, bronchodilators, and oxygen); longer observation periods may be required in patients who have experienced an infusion reaction. 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 an IV histamine-1 (H1) receptor antagonist (e.g., diphenhydramine) prior to the first dose or subsequent doses as deemed necessary. An interruption of the infusion and adjustments to the infusion rate are recommended if a mild to moderate infusion reaction occurs; severe infusion reactions necessitate immediate interruption and permanent discontinuation of therapy.
Use cetuximab with caution in patients with pre-existing pulmonary disease, as interstitial lung disease (ILD)/pneumonitis has been reported with cetuximab therapy, including one death. Monitor patients and interrupt cetuximab treatment for acute onset or worsening of pulmonary symptoms. Permanently discontinue cetuximab if a diagnosis of ILD is confirmed.
During clinical trials, cetuximab therapy was associated with dermatologic toxicities including acneiform rash as well as life-threatening and fatal bullous mucocutaneous disease with blisters, erosions, and skin sloughing. Subsequent to the development of severe dermatologic toxicities, complications including infection, S. aureus sepsis, and skin abscesses requiring incision and drainage have also been reported. Monitor patients for dermatologic toxicities and infectious sequelae; an interruption of therapy, dose reduction, or discontinuation of therapy may be necessary. It is recommended that patients limit sunlight (UV) exposure by wearing sunscreen and hats while receiving cetuximab and for 2 months after the last dose, as UV exposure can exacerbate any skin reaction that may occur.
Cardiac arrest, respiratory arrest, and/or sudden death have occurred in patients receiving cetuximab. Cautious use of cetuximab in combination with either radiation therapy or platinum-based therapy with 5-FU is warranted for head and neck cancer patients with a history of cardiac disease, specifically coronary artery disease, congestive heart failure, or cardiac arrhythmias. Although the etiology of these events is unknown, electrolyte imbalance may be a risk factor for serious cardiac events such as arrhythmia. Because the onset of electrolyte abnormalities may be days to months after the initiation of cetuximab therapy, closely monitor serum electrolytes for hypomagnesemia, hypocalcemia, and hypokalemia during treatment and for at least 8 weeks after completion of cetuximab therapy.
Studies have demonstrated the benefit of cetuximab in KRAS wild-type metastatic colorectal cancer (mCRC) only; cetuximab is not effective and is not indicated for the treatment of RAS mutant mCRC (KRAS mutations or NRAS mutations in exon 2 (codons 12 and 13), exon 3 (codons 59 and 61), and exon 4 (codons 117 and 146)). Assess KRAS mutational status using FDA-approved tests prior to treating mCRC patients with cetuximab.
Pregnancy should be avoided by females of reproductive potential during cetuximab treatment and for at least 2 months after the last dose. Although there are no adequately controlled studies in pregnant women, cetuximab can cause fetal harm or death when administered during pregnancy based on its mechanism of action and animal studies. Women who are pregnant or who become pregnant while receiving cetuximab should be apprised of the potential hazard to the fetus. In an animal reproduction study, IV administration of cetuximab (1 to 4 times the recommended human dose based on BSA) to pregnant cynomolgus monkeys during organogenesis resulted in an increased incidence of embryolethality and abortion. In mice, EGFR is critically important in reproductive and developmental processes including blastocyst implantation, placental development, and embryofetal/postnatal survival and development. Reduction or elimination of embryofetal or maternal EGFR signaling can prevent implantation, can cause embryofetal loss during various stages of gestation through effects on placental development, and can cause developmental anomalies and early death in surviving fetuses. Disruption or depletion of EGFR in animal models results in impaired placental, lung, cardiac, skin, and neural development.
Counsel patients about the reproductive risk and contraception requirements during cetuximab treatment. Cetuximab can cause loss of pregnancy if taken by the mother during pregnancy. Females of reproductive potential should avoid pregnancy and use effective contraception during and for at least 2 months after treatment with cetuximab. Females of reproductive potential should undergo pregnancy testing prior to initiation of cetuximab. Women who become pregnant while receiving cetuximab should be apprised of the potential hazard to the fetus. Although there are no data regarding the effect of cetuximab on human fertility, female infertility has been observed in animal studies.
Due to the potential for serious adverse reactions in nursing infants from cetuximab, advise women to discontinue breast-feeding during treatment and for 2 months after the final dose. It is not known whether cetuximab is present in human milk, although many drugs are excreted in human milk.
For the treatment of colorectal cancer:
-for the first-line treatment of KRAS wild-type, EGFR-expressing, metastatic colorectal cancer (mCRC) in combination with FOLFIRI (irinotecan, fluorouracil, leucovorin):
NOTE: Cetuximab is not indicated for the treatment of RAS mutant colorectal cancer or when the results of RAS mutation tests are unknown. In clinical trials, response rates did not correlate with either the percentage of EGFR positive cells or the intensity of EGFR expression. Confirm EGFR expression status and the absence of a RAS mutation by an FDA approved test prior to starting therapy at www.fda.gov/CompanionDiagnostics.
Intravenous dosage:
Adults: 400 mg/m2 IV on day 1 followed by weekly infusions of cetuximab 250 mg/m2 IV , administered 1 hour prior to chemotherapy, until disease progression or unacceptable toxicity; alternatively, cetuximab may be administered at a dose of 500 mg/m2 IV every 2 weeks. Administer in combination with the FOLFIRI regimen (irinotecan 180 mg/m2 IV over 30 to 90 minutes on day 1 followed by levoleucovorin 200 mg/m2 IV over 2 hours (or racemic leucovorin 400 mg/m2 IV), followed by fluorouracil 400 mg/m2 IV given as a bolus then 2,400 mg/m2 as a 46-hour continuous IV infusion, repeated every 14 days. In a multicenter, randomized, open-label, phase 3 clinical trial of patients with mCRC, unselected for KRAS mutational status, first-line treatment with cetuximab plus FOLFIRI (n = 599) significantly improved the primary endpoint of median progression-free survival (PFS) compared with FOLFIRI alone (n = 599) (8.9 months vs. 8 months); the overall response rate was 46.9% vs. 38.7%, respectively. Median overall survival was 19.9 months in the cetuximab group compared with 18.6 months in patients treated with FOLFIRI alone. In a subgroup analysis of patients with known KRAS mutational status (KRAS negative, n = 666; KRAS positive, n = 397), the addition of cetuximab to FOLFIRI therapy significantly improved the median PFS (9.9 vs. 8.4 months) and overall survival (23.5 vs. 20 months) times only in patients with KRAS wild type disease.
-for the first-line treatment of KRAS wild-type metastatic colorectal cancer (mCRC), in combination with mFOLFOX6 (leucovorin, oxaliplatin, fluorouracil)*:
NOTE: Cetuximab is not indicated for the treatment of RAS mutant colorectal cancer or when the results of RAS mutation tests are unknown. In clinical trials, response rates did not correlate with either the percentage of EGFR positive cells or the intensity of EGFR expression. Confirm EGFR expression status and the absence of a RAS mutation by an FDA approved test prior to starting therapy at www.fda.gov/CompanionDiagnostics.
Intravenous dosage:
Adults: 400 mg/m2 IV over 120 minutes (maximum infusion rate, 10 mg/minute) on day 1 followed by weekly infusions of cetuximab 250 mg/m2 IV over 60 minutes (maximum infusion rate, 10 mg/minute), administered 1 hour prior to chemotherapy, until disease progression or unacceptable toxicity in combination with the mFOLFOX6 regimen (oxaliplatin 85 mg/m2 IV concurrently via y-site with leucovorin 400 mg/m2 IV over 2 hours, followed by fluorouracil 400 mg/m2 IV given as a bolus and then 2,400 mg/m2 as a 46-hour continuous IV infusion, repeated every 14 days). First-line treatment with cetuximab plus modified FOLFOX (mFOLFOX) 4 or 6 significantly improved objective response rates (ORR) in patients with KRAS WT mCRC in two randomized clinical trials. The benefit to progression-free survival (PFS) was small to nonsignificant, and a benefit to overall survival (OS) was not demonstrated. Skin and gastrointestinal toxicities were increased in patients treated with cetuximab. Total exposure (AUC) to fluorouracil was similar when administered as two 22-hour infusions of 600 mg/m2, as in FOLFOX4, or as a single 46-hour infusion of 2,400 mg/m2, as in mFOLFOX6 in a pharmacokinetic study.
-for the treatment of KRAS wild-type, EGFR-expressing, metastatic colorectal cancer (mCRC) in combination with irinotecan in patients who are refractory to irinotecan-based chemotherapy:
NOTE: Cetuximab is not indicated for the treatment of RAS mutant colorectal cancer or when the results of RAS mutation tests are unknown. In clinical trials, response rates did not correlate with either the percentage of EGFR positive cells or the intensity of EGFR expression. Confirm EGFR expression status and the absence of a RAS mutation by an FDA approved test prior to starting therapy at www.fda.gov/CompanionDiagnostics.
Intravenous dosage:
Adults: 400 mg/m2 IV on day 1, followed by weekly infusions of cetuximab 250 mg/m2 IV until disease progression or unacceptable toxicity, in combination with irinotecan. Alternatively, cetuximab may be administered at a dose of 500 mg/m2 IV every 2 weeks. Multiple dosage regimens of irinotecan have been studied in combination with cetuximab, including irinotecan 180 mg/m2 IV once every 3 weeks; irinotecan 125 mg/m2 IV once weekly for 4 weeks out of 6; and, irinotecan 350 mg/m2 IV once every 3 weeks. In a multicenter clinical trial of patients with recurrent mCRC (tumor specimens not available for KRAS testing), patients were treated with cetuximab alone (n = 111) or cetuximab plus irinotecan (n = 218); in the irinotecan arm, the irinotecan dose and schedule was the same as the patient had previously failed. Of these patients, approximately 2/3 had previously failed oxaliplatin treatment. The objective response rate was 23% for patients treated with cetuximab plus irinotecan, versus 11% for those who received cetuximab alone; the median duration of response was 5.7 months vs. 4.2 months, and the median time to progression was 4.1 months versus 1.5 months, respectively. Response rates to combination therapy and monotherapy were similar for irinotecan refractory patients and patients who had failed both irinotecan and oxaliplatin.
-for the treatment of KRAS wild-type, EGFR-expressing, metastatic colorectal cancer (mCRC) as a single agent after failure of both irinotecan- and oxaliplatin-based regimens or in patients who are intolerant to irinotecan-based chemotherapy:
NOTE: Cetuximab is not indicated for the treatment of RAS mutant colorectal cancer or when the results of RAS mutation tests are unknown. In clinical trials, response rates did not correlate with either the percentage of EGFR positive cells or the intensity of EGFR expression. Confirm EGFR expression status and the absence of a RAS mutation by an FDA approved test prior to starting therapy at www.fda.gov/CompanionDiagnostics.
Intravenous dosage:
Adults: 400 mg/m2 IV on day 1, followed by weekly infusions of 250 mg/m2 IV until disease progression or unacceptable toxicity. Alternatively, cetuximab may be administered at a dose of 500 mg/m2 IV every 2 weeks. In a multicenter, randomized, open-label clinical trial of patients with previously treated, recurrent mCRC, cetuximab monotherapy (n = 287) significantly improved median overall survival compared with best supportive care (n = 285) (6.1 months vs. 4.6 months); in the subset of patients with KRAS wild-type tumors (n = 245), cetuximab monotherapy also improved overall survival (8.6 months vs. 5 months).
-for the treatment of BRAF mutation-positive, RAS wild-type, metastatic colorectal cancer, in combination with irinotecan and vemurafenib*:
Intravenous dosage:
Adults: 500 mg/m2 IV plus irinotecan (180 mg/m2 IV) on day 1, every 14 days, in combination with vemurafenib 960 mg by mouth twice daily, until disease progression or unacceptable toxicity. Reduce the dose of irinotecan by at least one dose level in patients who are homozygous for the UGT1A1*28 allele. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. In a multicenter, randomized, open-label phase 2 clinical trial, treatment with vemurafenib, cetuximab and irinotecan significantly improved the median progression-free survival (PFS) over treatment with cetuximab plus irinotecan, without vemurafenib (4.4 months vs. 2 months) in patients with BRAF V600E mutation-positive, RAS wild-type, metastatic colorectal cancer (mCRC) received treatment with cetuximab and irinotecan, with or without vemurafenib (a BRAF inhibitor). Approximately 50% of patients in the control arm crossed over to receive vemurafenib after progression; the rate of disease control was also significantly improved in the vemurafenib arm (67% vs. 22%).
-for the treatment of previously treated metastatic colorectal cancer (mCRC) in patients with a BRAF V600E mutation, in combination with encorafenib:
NOTE: Confirm the BRAF V600E mutation prior to starting therapy. Information on FDA-approved tests for the detection of BRAF V600E mutations is available at www.fda.gov/CompanionDiagnostics.
Intravenous dosage:
Adults: 400 mg/m2 IV over 120 minutes on day 1 followed by weekly infusions of cetuximab 250 mg/m2 IV over 60 minutes in combination with encorafenib until disease progression or unacceptable toxicity. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. If cetuximab is discontinued, also discontinue encorafenib. Treatment with encorafenib plus cetuximab significantly improved overall survival (9.3 months vs. 5.9 months), overall response rate (20% vs. 2%; complete response, 3% vs. 0%), and progression-free survival (4.3 months vs. 1.5 months) compared with either irinotecan plus cetuximab or FOLFIRI plus cetuximab in patients with previously treated BRAF V600E mutation-positive metastatic colorectal cancer in a randomized, open-label, phase 3 trial (BEACON); the median duration of response was 6.1 months in the encorafenib arm.
For the treatment of head and neck cancer:
NOTE: Cetuximab is designated as an orphan drug by the FDA for the treatment of squamous cell cancer of the head and neck in patients who express EGFR.
-for the first-line treatment of locally or regionally advanced squamous cell head and neck cancer, in combination with radiation therapy:
NOTE: Progression-free survival was not improved when cetuximab was added to radiation therapy plus cisplatin for the treatment of locally advanced squamous cell head and neck cancer in a controlled study (n = 940); grade 3 and 4 toxicity and adverse reactions with fatal outcomes occurred more often in cetuximab-treated patients in this study.
Intravenous dosage:
Adults: 400 mg/m2 IV as an initial loading dose 1 week prior to initiation of a course of radiation therapy, followed by weekly infusions of cetuximab 250 mg/m2 IV for the duration of radiation therapy (6 to 7 weeks). Complete cetuximab administration 1 hour before radiation therapy. In a randomized clinical trial of patients with locally or regionally advanced squamous cell head and neck cancer (n = 424), treatment with cetuximab plus radiation therapy significantly improved the median duration of locoregional control (24.4 months vs. 14.9 months) and overall survival (49 months vs. 29.3 months) compared with radiation therapy alone.
-for the first-line treatment of recurrent locoregional disease or metastatic squamous cell head and neck cancer, in combination with platinum-based chemotherapy and fluorouracil:
Intravenous dosage:
Adults: 400 mg/m2 IV as an initial loading dose on day 1 followed by weekly infusions of cetuximab 250 mg/m2 IV, administered 1 hour prior to chemotherapy, until disease progression or unacceptable toxicity; alternatively, cetuximab may be administered at a dose of 500 mg/m2 IV every 2 weeks. Complete cetuximab administration 1 hour prior to chemotherapy. Administer in combination with cisplatin (100 mg/m2 IV on day 1) or carboplatin (AUC 5 IV on day 1) plus fluorouracil (1,000 mg/m2 IV on days 1, 2, 3, and 4), repeated every 3 weeks for up to 6 cycles. In a randomized, open-label clinical trial of patients with no prior therapy for recurrent locoregional disease or metastatic head and neck cancer (n = 442), the addition of cetuximab to platinum-based chemotherapy plus fluorouracil significantly improved median overall survival (OS) (10.1 months vs. 7.4 months), median progression-free survival (PFS) (5.5 months vs. 3.3 months), and objective response rate (35.6% vs. 19.5%) compared with chemotherapy alone. In exploratory subgroup analyses by initial platinum therapy, the difference in median OS was 3.3 months for patients receiving cetuximab plus cisplatin/fluorouracil and 1.4 months for patients receiving cetuximab plus carboplatin/fluorouracil compared to platinum/fluorouracil alone; the difference in median PFS with the addition of cetuximab compared to chemotherapy alone was 2.1 months and 1.7 months, respectively.
-for the treatment of recurrent or metastatic squamous cell cancer of the head and neck when prior platinum-based therapy has failed, as monotherapy:
Intravenous dosage:
Adults: 400 mg/m2 IV on day 1 followed by weekly infusions of 250 mg/m2 IV until disease progression or unacceptable toxicity. Alternatively, cetuximab may be administered at a dose of 500 mg/m2 IV every 2 weeks until disease progression or unacceptable toxicity. In a multicenter, noncomparative trial of patients with recurrent or metastatic squamous cell head and neck cancer with progression within 30 days of platinum-based chemotherapy (n = 103), treatment with cetuximab resulted in an objective response rate of 13% for a median duration of 5.8 months.
-for the treatment of recurrent or metastatic squamous cell carcinoma of the head and neck in combination with cisplatin*:
Intravenous dosage:
Adults: 400 mg/m2 IV over 120 minutes (maximum infusion rate, 10 mg/minute) on day 1, followed by weekly infusions of cetuximab 250 mg/m2 IV over 60 minutes (maximum infusion rate, 10 mg/minute), in combination with cisplatin (100 mg/m2 IV on day 1), repeated every 4 weeks until disease progression or for 2 treatment cycles after the achievement of a complete response. In a phase 3 clinical trial of patients with recurrent or metastatic head and neck cancer (n = 117), neither progression-free survival (4.2 months vs. 2.7 months) nor overall survival (9.2 months vs. 8 months) were significantly improved with the addition of cetuximab; however the objective response rate was significantly improved (26% vs. 10%).
For the first-line treatment of advanced non-small cell lung cancer (NSCLC)* in combination with cisplatin and vinorelbine:
Intravenous dosage:
Adults: 400 mg/m2 IV over 2 hours (maximum infusion rate: 10 mg/minute) the first week with subsequent weekly infusions of 250 mg/m2 IV over 60 minutes (maximum infusion rate: 10 mg/minute) until disease progression or unacceptable toxicity, in combination with up to 6 cycles of cisplatin (80 mg/m2 IV) on day 1 and vinorelbine (25 mg/m2 IV) on days 1 and 8 repeated every 21 days. In a phase 3 trial of 1,125 patients with advanced EGFR-detectable non-small cell lung cancer, the addition of cetuximab to the doublet cisplatin and vinorelbine significantly improved the primary end point overall survival (11.3 months vs. 10.1 months), response rate (36% vs. 29%), and time to treatment failure (4.2 months vs. 3.7 months). Patients who received cetuximab had a significantly higher incidence of febrile neutropenia (22% vs. 15%). A subgroup analysis of patients who developed a rash within the first 21 days of treatment, revealed a positive correlation between outcomes and the development of a first cycle rash. Multiple previous trials of EGFR-targeted tyrosine kinase inhibitors in combination with chemotherapy in the front-line treatment of patients with non-small cell lung cancer have generally shown no additional survival benefit with the addition of the tyrosine kinase inhibitor. Consideration should be given to the use of molecular markers to aid in patient selection as further information about this practice continues to become available.
Therapeutic Drug Monitoring:
Dosage Adjustments for Treatment-Related Toxicities
Infusion-Related Reactions
-Grade 1 or 2: Reduce the cetuximab infusion rate by 50%.
-Grade 3 or 4: Immediately and permanently discontinue cetuximab therapy.
Dermatologic toxicities and infectious sequelae (e.g., acneiform rash, mucocutaneous disease)
-Grade 3 or 4, first occurrence: Delay infusion for 1 to 2 weeks. If rash improves, continue cetuximab therapy without a dose reduction; if rash does not improve, discontinue cetuximab therapy.
-Grade 3 or 4, second occurrence: Delay infusion for 1 to 2 weeks. If rash improves, continue therapy and reduce the dose of cetuximab to 200 mg/m2 IV weekly; if rash does not improve, discontinue cetuximab therapy.
-Grade 3 or 4, third occurrence: Delay infusion for 1 to 2 weeks. If rash improves, continue therapy and reduce the dose of cetuximab to 150 mg/m2 IV weekly; if rash does not improve, discontinue cetuximab therapy.
-Grade 3 or 4, fourth occurrence: Discontinue cetuximab therapy.
Pulmonary toxicity
-Acute onset or worsening of pulmonary symptoms: Delay infusion for 1 to 2 weeks. If condition improves, continue cetuximab therapy at the dose that was being administered at the time of occurrence. If condition does not improve, or if interstitial lung disease (ILD) is confirmed, discontinue cetuximab.
Maximum Dosage Limits:
-Adults
400 mg/m2 IV for the initial dose then 250 mg/m2 IV once weekly for subsequent doses; OR 500 mg/m2 IV every 2 weeks.
-Geriatric
400 mg/m2 IV for the initial dose then 250 mg/m2 IV once weekly for subsequent doses; OR 500 mg/m2 IV every 2 weeks.
-Adolescents
Safety and efficacy have not been established.
-Children
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.
Patients with Renal Impairment Dosing
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.
Cisplatin: (Major) Cetuximab is not indicated for the treatment of squamous cell cancer of the head and neck (SCCHN) in combination with radiation and cisplatin due to the risk of increased serious adverse reactions. In a controlled study of patients with locally advanced SCCHN (n = 940), treatment with cetuximab in combination with radiation therapy and cisplatin increased the incidence of grade 3 and 4 mucositis, radiation recall syndrome, acneiform rash, cardiac events, and electrolyte disturbances compared to radiation and cisplatin alone. Myocardial ischemia occurred in 2% of patients in the cetuximab arm compared with 0.9% in the control arm; adverse reactions with fatal outcome were reported in 4% in the cetuximab arm and 3% in the control arm. The addition of cetuximab to radiation and cisplatin did not improve progression free survival.
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.
Cetuximab is a recombinant human/mouse chimeric monoclonal antibody that binds specifically to the extracellular domain of the human epidermal growth factor receptor (EGFR). It is composed of the Fv regions of a murine anti-EGFR antibody with human IgG1 heavy and kappa light chain constant regions, and is produced in a mammalian (murine myeloma) cell culture. The EGFR is a transmembrane glycoprotein that is a member of a subfamily of type 1 receptor tyrosine kinases including EGFR, HER2, HER3, and HER4. It is constitutively expressed in many normal epithelial tissues, including the skin and hair follicle, but is also detected in many human cancers including those of the head and neck, colon, and rectum.
Cetuximab binds to EGFR on both normal and tumor cells, competitively inhibiting 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 (VEGF) production. Signal transduction through EGFR activates wild-type Ras proteins; however, 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 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.
Induction of EGFR-mediated MAPK pathway activation has been identified as a mechanism of resistance to BRAF inhibitors in patients with BRAF-mutant colorectal cancer. In nonclinical models, combinations of a BRAF inhibitor with an EGFR inhibitor have been shown to overcome this resistance mechanism. Coadministration of cetuximab with encorafenib had an antitumor effect greater than either drug alone in a mouse model of colorectal cancer with mutated BRAF V600E.
Cetuximab is administered as an IV infusion and exhibits nonlinear pharmacokinetics when administered both as monotherapy or in combination with chemotherapy. The volume of distribution (Vd) approximates the vascular space of 2 to 3 Liters/m2 and appears to be independent of dose. Steady-state is reached by the third weekly infusion when administered at the recommended dose regimen (400 mg/m2 initial dose, followed by 250 mg/m2 once weekly); the mean half-life was approximately 112 hours (range, 63 to 230 hours). Clearance of cetuximab decreased from 0.08 Liters/hour/m2 to 0.02 Liters/hour/m2 as the dose increased from 20 mg/m2 to 200 mg/m2.
-Route-Specific Pharmacokinetics
Intravenous Route
The AUC increased in a greater than dose proportional manner as the dose increased from 20 mg/m2 to 200 mg/m2; at doses greater than 200 mg/m2, the AUC appeared to plateau. Mean peak (Cmax) concentrations across studies ranged from 168 mcg/mL to 235 mcg/mL, while mean trough (Cmin) concentrations ranged from 41 mcg/mL to 85 mcg/mL when administered at the recommended dose regimen (400 mg/m2 initial dose, followed by 250 mg/m2 once weekly). In a population pharmacokinetic analysis from two clinical trials, cetuximab had an approximately 22% (90% confidence interval, 6% to 38%) higher systemic exposure compared to EU-approved cetuximab.
-Special Populations
Hepatic Impairment
Hepatic function did not have a clinically significant effect on the pharmacokinetics of cetuximab.
Renal Impairment
Renal function did not have a clinically significant effect on the pharmacokinetics of cetuximab.
Pediatrics
The pharmacokinetics of cetuximab in pediatric patients age 1 to 12 years (n = 9) were similar to pediatric patients age 13 to 18 years (n = 6) at the 75 mg/m2 and 150 mg/m2 single dose levels in an open-label, single-arm, dose-finding study of pediatric patients with refractory solid tumors receiving concomitant irinotecan. The volume of distribution appeared to be independent of dose and approximated the vascular space of 2 to 3 Liters/m2. Following a single dose of 150 mg/m2, the geometric mean AUC (CV%) was 17.7 mg x hour/mL (34%) in the younger age group and 13.4 mg x hour/mL in the adolescent group; the mean half-life was 110 hours (range, 69 to 188 hours) and 82 hours (range, 55 to 117 hours), respectively.
Geriatric
Age did not have a clinically significant effect on the pharmacokinetics of cetuximab.
Gender Differences
Gender did not have a clinically significant effect on the pharmacokinetics of cetuximab.
Ethnic Differences
Ethnicity did not have a clinically significant effect on the pharmacokinetics of cetuximab.
Obesity
Clearance of cetuximab increased by 1.8-fold as body surface area increased from 1.3 m2 to 2.3 m2, which is consistent with the recommended dosing of cetuximab on a mg/m2 basis.