Cetuximab, a recombinant chimeric (human-murine) monoclonal antibody that binds to epidermal growth factor receptors (EGFR), is an antineoplastic agent.1, 6, 7
Patients enrolled in clinical studies for the use of cetuximab for colorectal cancer were required to have immunohistochemical (IHC) evidence of epidermal growth factor receptor (EGFR) expression; however, response rates in these clinical studies did not correlate with either the percentage of positive cells or the intensity of EGFR expression.1, 6, 29 In addition, responses to cetuximab therapy have been observed in patients with EGFR-negative colorectal cancer.22, 30 Some authorities state that routine EGFR expression testing is not recommended in patients with colorectal cancer and that patients should not be included or excluded from cetuximab therapy based solely on EGFR test results.31
Because retrospective stratified analyses of metastatic colorectal cancer trials have not shown a treatment benefit for cetuximab in patients whose tumors had KRAS mutations in codon 12 or 13, use of the drug is not recommended for the treatment of colorectal cancer with such mutations. 28, 35, 37 (See KRAS Testing in Patients Receiving Cetuximab for Colorectal Cancer under Uses: Colorectal Cancer.)
Cetuximab Monotherapy for Advanced Colorectal Cancer
Cetuximab is used as a single agent for the treatment of EGFR-expressing metastatic colorectal cancer in patients with disease that has failed treatment with both irinotecan-based and oxaliplatin-based regimens.1 Cetuximab also is used as a single agent for the treatment of EGFR-expressing, metastatic colorectal cancer in patients who are intolerant of irinotecan-based chemotherapy.1, 11
The current indication for cetuximab monotherapy for recurrent EGFR-expressing metastatic colorectal cancer is based mainly on the results of a multicenter, open-label, randomized trial in 572 patients receiving either cetuximab and best supportive care or best supportive care alone for EGFR-expressing metastatic colorectal cancer.1, 25 All patients had progression of disease following previous treatment with an irinotecan-containing regimen and an oxaliplatin-containing regimen or had contraindications to treatment with these agents.1, 25 The treatment regimen consisted of an initial dose of cetuximab 400 mg/m2 as a 2-hour IV infusion followed by cetuximab 250 mg/m2 as a 1-hour IV infusion weekly until disease progression or unacceptable toxicity occurred.1, 25 The median age of the patients was 63 years, 64% were male, and most of the patients (89%) were Caucasian; 77% had a baseline ECOG performance status of 0-1.1
Median overall survival was prolonged in patients receiving cetuximab and best supportive care compared with those receiving best supportive care alone (6.1 versus 4.6 months; hazard ratio for death 0.77 with a 95% confidence interval of 0.64-0.92).1, 25 Adverse effects were more frequent in patients receiving cetuximab therapy and best supportive care than in those receiving best supportive care alone, particularly rash/desquamation (89 versus 16%, grade 3 or 4 in 12 versus less than 1%).1, 25
Cetuximab and Irinotecan for Advanced Colorectal Cancer
Cetuximab is used in combination with irinotecan for the treatment of EGFR-expressing metastatic colorectal cancer that is refractory to irinotecan-based chemotherapy.1 The indication for cetuximab in combination with irinotecan for EGFR-expressing, metastatic colorectal cancer is based on objective response rates; there currently are no data demonstrating a clinical benefit (e.g., improvement in disease-related symptoms, increased survival).1
The current indication for cetuximab in combination with irinotecan is based principally on the results of a phase 2, multicenter, randomized, controlled study that compared safety and efficacy of cetuximab monotherapy with the combination regimen of cetuximab and irinotecan.1, 3
This phase 2 study enrolled 329 patients with EGFR-expressing, metastatic colorectal cancer refractory to irinotecan-based chemotherapy; approximately two thirds of enrolled patients had previously failed oxaliplatin therapy.1, 3 In this study, 111 patients were randomized to receive cetuximab monotherapy (400 mg/m2 initially, followed by 250 mg/m2 weekly until disease progression or unacceptable toxicity occurred), and 218 patients were randomized to receive cetuximab (at the same dosage) in combination with irinotecan (350 mg/m2 every 3 weeks, 180 mg/m2 every 2 weeks, or 125 mg/m2 weekly for 4 doses every 6 weeks).1, 3
The overall response rate (complete plus partial responses) was higher in patients receiving the combination regimen (about 23%) than in those receiving cetuximab monotherapy (about 11%).1, 3, 6, 7 In addition, median time to radiographic disease progression and median duration of response were longer in patients receiving the combination regimen (4.1 and 5.7 months, respectively) than in those receiving cetuximab alone (1.5 and 4.2 months, respectively).1, 3 Median survival was not substantially different between the 2 groups (8.6 months for the combination regimen versus 6.9 months for cetuximab monotherapy).3
Cetuximab and Combination Chemotherapy as First-line Therapy for Metastatic Colorectal Cancer
Cetuximab has been used with combination chemotherapy regimens for the first-line treatment of metastatic colorectal cancer.20
20, 21 In a phase 3 randomized trial that enrolled 238 patients with previously untreated metastatic colorectal cancer before closing early because of slow accrual, the addition of cetuximab to either FOLFIRI (irinotecan/fluorouracil/leucovorin) or FOLFOX (oxaliplatin/fluorouracil/leucovorin) appeared to increase response rates; at a median follow-up of about 1 year, analysis of the data did not show any effect of the addition of cetuximab on progression-free survival or duration of response.20 A phase 3 randomized trial comparing the addition of cetuximab, bevacizumab, or both to combination chemotherapy (FOLFOX or FOLFIRI) for the first-line treatment of metastatic colorectal cancer is under way.21
KRAS Testing in Patients Receiving Cetuximab for Colorectal Cancer
The presence of mutations in the KRAS (also called K-ras ) gene in codon 12 or 13 in colorectal cancer tumor tissue has been associated with a lack of benefit from therapy with anti-EGFR monoclonal antibodies (e.g., cetuximab, panitumumab); such mutations appear to be present in approximately 30-50% of primary colorectal tumors.26, 28, 33, 35, 36, 37, 38, 39, 40, 41, 42, 43 Retrospective subset analyses from 7 randomized clinical studies evaluating cetuximab or panitumumab either as monotherapy or in combination with chemotherapy in metastatic colorectal cancer suggest that these anti-EGFR monoclonal antibodies are not effective for the treatment of patients with colorectal cancer containing KRAS mutations in codon 12 or 13.28, 33, 34, 37, 43 The American Society of Clinical Oncology (ASCO)28 and some clinicians31, 36, 38, 39, 40, 41, 42, 43 recommend that all patients with metastatic colorectal cancer who are potential candidates for EGFR inhibitor therapy (e.g., cetuximab, panitumumab) have their tumor tested for KRAS mutations28, 31, 36, 38, 39, 40, 41, 42, 43 in a Clinical Laboratory Improvement Amendments (CLIA)-accredited laboratory.28, 31 If KRAS mutation in codon 12 or 13 is detected, the use of cetuximab is not recommended.28, 31, 36
Because expression of EGFR has been detected in nearly all head and neck cancers, patients enrolled in the studies on which the labeled indications for cetuximab for this neoplasm were based were not required to have immunohistochemical evidence of EGFR expression.1
Cetuximab and Radiation Therapy for Locally or Regionally Advanced Disease
Cetuximab is used in combination with radiation therapy for the initial treatment of locally or regionally advanced squamous cell carcinoma of the head and neck, particularly for patients who cannot tolerate platinum-based chemotherapy with radiation therapy.1, 13
In a multicenter randomized controlled trial, 424 patients with stage III or IV squamous cell carcinoma of the oropharynx (60%), larynx (25%), or hypopharynx (15%) received initial treatment with either cetuximab and radiation therapy or radiation therapy alone.1, 9 Stratification factors were Karnofsky performance status (60-80 versus 90-100), nodal stage (N0 versus N+), tumor stage (T1-3 versus T4 according to AJCC 1998 staging criteria), and radiation therapy fractionation (concomitant boost, once daily, or twice daily).1, 9
Patients receiving cetuximab were given premedication with IV diphenhydramine hydrochloride 50 mg or an equivalent histamine H1-receptor antagonist to reduce the risk of infusion-related reactions.1, 9 Patients receiving cetuximab were given a 20-mg test dose of the drug on day 1; an initial dose of cetuximab 400 mg/m2 was administered by 2-hour IV infusion 1 week before the initiation of radiation therapy followed by cetuximab 250 mg/m2 by 1-hour IV infusion 1 hour prior to radiation therapy once weekly for 6-7 weeks.1, 9 Radiation therapy was administered for 6-7 weeks as concomitant boost (56%), once daily fractionation (26%), or twice daily fractionation (18%).1, 9 For patients with stage N1 or higher neck disease, neck dissection at 4-8 weeks following completion of radiation therapy was recommended.9 The patients enrolled in the trial were mostly Caucasian men with a baseline Karnofsky performance status of at least 80; the median age of the patients was 57 years.1, 9
Patients with locally or regionally advanced squamous cell carcinoma of the head and neck receiving cetuximab and radiation therapy had prolonged median duration of locoregional control (24 versus 15 months, hazard ratio for locoregional progression or death: 0.68) and prolonged median overall survival (49 versus 29 months, hazard ratio for death: 0.74) compared with those receiving radiation therapy alone.1, 9 Subgroup analysis according to tumor type suggested efficacy of cetuximab and radiation therapy for oropharyngeal tumors, but not for hypopharyngeal or laryngeal tumors.9, 13 Acneiform rash (all grades: 87 versus 10%, grade 3 or 4: 17 versus 1%) and infusion reactions (all grades: 15 versus 2%, grade 3 or 4: 3 versus 0%) occurred more frequently in patients receiving cetuximab and radiation therapy than in those receiving radiation therapy alone.1, 9
The use of platinum-based chemotherapy with radiation therapy is the current standard of care for the treatment of advanced head and neck cancer.13 Further study is needed to compare the efficacy and toxicity for cetuximab and radiation therapy versus platinum-based chemotherapy and radiation therapy.13
Monotherapy for Advanced Disease
Cetuximab is used alone for the treatment of recurrent or metastatic squamous cell carcinoma of the head and neck in patients with disease that has failed platinum-based therapy.1
The current indication for use of cetuximab as a single agent for the treatment of recurrent or metastatic squamous cell carcinoma of the head and neck is based principally on the results of a single-arm, multicenter clinical trial involving 103 patients with disease that progressed within 30 days following 2-6 cycles of platinum-based chemotherapy.1, 12 Patients received a 20-mg test dose of cetuximab on day 1, an initial dose of cetuximab 400 mg/m2, and then cetuximab 250 mg/m2 once weekly until disease progression or unacceptable toxicity.1, 12 The patients enrolled in the trial were mostly Caucasian men, and 62% of the patients had a baseline Karnofsky performance status of at least 80; the median age of the patients was 57 years.1, 12
The objective response rate was 13% and the median duration of response was 5.8 months for patients receiving cetuximab monotherapy for recurrent or metastatic head and neck cancer.1, 12
Cetuximab and Chemotherapy With or Without Radiation Therapy for Advanced Disease
Cetuximab has been used in combination with chemotherapy, with or without radiation therapy†, for the treatment of recurrent or metastatic squamous cell carcinoma of the head and neck.5
In two phase 2 studies, cetuximab with platinum-based chemotherapy demonstrated activity in the treatment of recurrent or metastatic platinum-refractory squamous cell carcinoma of the head and neck.14, 15 In a phase 3 randomized trial, the addition of cetuximab to cisplatin improved response rates but did not affect progression-free survival or overall survival in patients receiving first-line treatment for recurrent or metastatic squamous cell carcinoma of the head and neck.5 In another phase 3 randomized trial, the addition of cetuximab to a platinum agent (cisplatin or carboplatin) and fluorouracil prolonged median overall survival (10.1 versus 7.4 months) and median progression-free survival (5.6 versus 3.3 months) and increased the response rate (36 versus 20%) in the first-line treatment of recurrent and/or metastatic squamous cell cancer of the head and neck.16 Grade 3 or 4 adverse effects that occurred more frequently in patients receiving cetuximab with a platinum agent and fluorouracil than in those receiving a platinum agent and fluorouracil included skin reactions (grade 3 only, in 9 versus less than 1%), hypomagnesemia and anorexia (each in 5 versus 1%), and sepsis, including septic shock (in 4 versus less than 1%).16
In a pilot study, cetuximab and cisplatin were administered with delayed, accelerated (concomitant boost) fractionation radiation therapy for the treatment of locoregionally advanced squamous cell head and neck cancer.17 The study was closed early because of safety concerns regarding fatalities and serious adverse events.17 Of the 21 patients enrolled in the study, one patient died from pneumonia and one patient died of an unknown cause.1, 17 Four patients discontinued treatment because of adverse events; adverse cardiac events were the reason for discontinuation of treatment in two of these patients with myocardial infarction in one patient and arrhythmia, diminished cardiac output, and hypotension in another patient.1 Although use of this regimen is not recommended outside of a clinical trial because of safety concerns, high rates of response and high 3-year survival rates suggest that further study of cetuximab in combined modality treatment for advanced head and neck cancer is warranted.17
A phase 3 randomized trial studying the effect of the addition of cetuximab to a regimen of concurrent accelerated fractionated radiation therapy and cisplatin for stage III or IV squamous cell carcinoma of the oropharynx, hypopharynx, or larynx is under way.18
Efficacy and safety of cetuximab in combination with various chemotherapy regimens as first-line therapy for advanced (stage IIIB [with malignant pleural effusion] or IV [metastatic]) non-small cell lung cancer (NSCLC)† has been studied in several randomized studies.10001, 10002, 10004, 10006, 10019
Use of cetuximab either concurrently with or following carboplatin and paclitaxel therapy was investigated in a randomized phase 2 study (S0342) in 242 patients with previously untreated stage IIIB or IV NSCLC.10004 Patients in both treatment groups received carboplatin (at the dose required to obtain an area under the plasma concentration-time curve [AUC] of 6 mg/mL per minute) and paclitaxel (225 mg/m2 by IV infusion) in 21-day cycles for 4 cycles; cetuximab (initial dose of 400 mg/m2 by IV infusion followed by 250 mg/m2 by IV infusion once weekly) was initiated either concurrently with or following completion of carboplatin and paclitaxel therapy and was continued until disease progression, unacceptable toxicity, or withdrawal of patient consent.10004 At a median follow-up of 32 months, overall survival (10.9 versus 10.7 months), progression-free survival (4.3 versus 4.4 months), and response rates (32 versus 30%) were similar in both treatment groups; however, the incidence of grade 3/4 sensory neuropathy was higher in patients receiving concurrent therapy compared with those receiving sequential therapy (15 versus 5%, respectively).10004 About one-third of patients underwent EGFR testing (using fluorescent in situ hybridization [FISH] methodology); those with EGFR-positive tumors had longer median progression-free survival (6 versus 3 months) and overall survival (15 versus 7 months) compared with those with EGFR-negative tumors.10005 Overall survival favored EGFR-positive patients receiving cetuximab concurrently with chemotherapy.10005
Efficacy and safety of cetuximab administered concurrently with up to 6 cycles of chemotherapy and then continued alone as maintenance therapy have been evaluated in two phase 3, open-label, randomized studies (First-line Erbitux in Lung Cancer [FLEX] and BMS-099) in patients with previously untreated stage IIIB or IV NSCLC.10001, 10002 Patients in these studies received either cetuximab and chemotherapy (either cisplatin and vinorelbine or carboplatin and a taxane) or chemotherapy alone.10001, 10002 The studies included patients with any histologic cell type but excluded those with metastatic CNS disease and those who had received prior anti-EGFR therapy.10001, 10002 Patient enrollment in the BMS-099 study was independent of EGFR expression status, while enrollment in the FLEX study required immunohistochemical (IHC) evidence of EGFR expression (using the Dako EGFR pharmDx® test kit).10001, 10002 In the BMS-099 study, patients were stratified according to their baseline ECOG performance status (0 or 1), intended taxane (paclitaxel or docetaxel), and study site.10002
In the FLEX study, 1125 patients were randomized to receive vinorelbine (25 mg/m2 by IV infusion on days 1 and 8) and cisplatin (80 mg/m2 by IV infusion on day 1) in 21-day cycles either alone or in combination with cetuximab (initial dose of 400 mg/m2 as a 2-hour IV infusion on day 1 followed by 250 mg/m2 by IV infusion over 1 hour once weekly); cetuximab was continued until disease progression or unacceptable toxicity occurred, while vinorelbine and cisplatin were administered for up to 6 cycles.10001 In the BMS-099 study, 676 patients were randomized to receive carboplatin (administered on day 1 at the dose required to obtain an AUC of 6 mg/mL per minute) and a taxane (paclitaxel 225 mg/m2 as a 3-hour IV infusion or docetaxel 75 mg/m2 as a 1-hour IV infusion on day 1) in 21-day cycles either alone or in combination with cetuximab (initial dose of 400 mg/m2 as a 2-hour IV infusion followed by 250 mg/m2 by IV infusion over 1 hour once weekly); cetuximab was continued until disease progression or unacceptable toxicity occurred, while carboplatin and a taxane were administered for up to 6 cycles.10002
In the FLEX study, the primary measure of efficacy was overall survival.10001 At a median follow-up of 23.8 months, median overall survival was 1.2 months longer (11.3 versus 10.1 months; hazard ratio of 0.87) and the rate of survival at 1 year was higher (47 versus 42%) for patients receiving cetuximab in combination with cisplatin and vinorelbine compared with those receiving cisplatin and vinorelbine alone.10001 Median progression-free survival was 4.8 months in both treatment groups.10001 The overall response rate was 36% for patients receiving cetuximab in combination with chemotherapy and 29% for those receiving chemotherapy alone.10001 Subset analysis suggested that ECOG performance status, smoking status, histologic type, gender, and age did not influence the treatment effect on overall survival.10001
Subset analysis of the FLEX study results based on ethnicity indicated that characteristics associated with a more favorable prognosis (i.e., adenocarcinoma histology, female gender, never smoked) were more common in Asian patients than in Caucasian patients and that the median survival of Asian patients was 10 months longer than that of Caucasian patients.10001 However, a higher proportion of Asian patients received oral tyrosine kinase inhibitors following their assigned study treatment, and the possibility that additional EGFR-targeted therapy might have contributed to an improved survival rate for these patients cannot be ruled out.10001 The addition of cetuximab to chemotherapy did not significantly improve survival of Asian patients or other non-Caucasian patients.10001 In contrast, median overall survival of Caucasian patients (84% of patients in the study) was longer for those receiving cetuximab in combination with chemotherapy compared with those receiving chemotherapy alone (10.5 versus 9.1 months).10001 Subset analysis based on tumor histology indicated that median survival times for patients receiving cetuximab in combination with chemotherapy compared with those receiving chemotherapy alone were 12 versus 10.3 months, respectively, for patients with adenocarcinoma and 10.2 versus 8.9 months, respectively, for those with squamous cell carcinoma.10001
In the FLEX study, grade 3 or 4 febrile neutropenia (22 versus 15%), acneiform rash (10 versus less than 1%), infusion-related reactions (4 versus 1%), and diarrhea (5 versus 2%) occurred more frequently in patients receiving cetuximab in combination with cisplatin and vinorelbine than in those receiving cisplatin and vinorelbine alone.10001
In the BMS-099 study, the primary measure of efficacy was progression-free survival assessed by an independent radiologic review committee.10002 The addition of cetuximab to carboplatin and taxane therapy improved the overall response rate (25.7 versus 17.2%) but did not substantially improve median progression-free survival (4.4 versus 4.2 months) or median overall survival (9.7 versus 8.4 months).10002 Subgroup analyses suggested that the addition of cetuximab to chemotherapy had a greater effect on progression-free survival in certain subgroups of patients (those with an ECOG performance status of 0, those receiving docetaxel, and those with squamous cell histology) than in the overall study population; however, similar trends were not observed for overall survival.10002 Grade 3 or 4 acneiform rash (10.5 versus 0%), infusion-related reactions (4.6 versus 0.9%), hypomagnesemia (8.8 versus 0.7%), diarrhea (5.2 versus 2.5%), dehydration (8.6 versus 4.7%), and neutropenia (62.5 versus 56%) occurred more frequently in patients receiving cetuximab in combination with carboplatin and a taxane than in those receiving carboplatin and a taxane alone.10002
Post-hoc analyses of the FLEX and BMS-099 studies were performed in an attempt to identify tumor markers that would predict which patients might benefit from the addition of cetuximab to chemotherapy as first-line treatment for advanced NSCLC.10016, 10017, 10018 Comparisons of outcomes between treatment groups according to tumor marker status revealed no significant associations between efficacy (i.e., overall survival, progression-free survival, tumor response) and KRAS mutation status, EGFR mutation status, EGFR gene copy number (assessed by FISH methodology), or phosphatase and tensin homolog (PTEN) gene expression (assessed by IHC methodology) that would identify patients who might benefit from receiving cetuximab in addition to chemotherapy.10016, 10017 In the BMS-099 study, EGFR expression (assessed by IHC methodology and described as either positive or negative) was not associated with improved efficacy for cetuximab and chemotherapy compared with chemotherapy alone.10017 However, in the FLEX study, addition of cetuximab to chemotherapy was associated with a survival benefit in patients with high EGFR expression (IHC score of 200 or greater on a scale of 0-300); among patients with high EGFR expression, overall survival was 12 months for those receiving cetuximab and chemotherapy compared with 9.6 months for those receiving chemotherapy alone.10018
Although combined therapy with cetuximab and chemotherapy prolonged overall survival in the FLEX study, the magnitude of the benefit was modest and the same benefit was not observed in the BMS-099 study; in addition, combined therapy did not prolong progression-free survival in either study.10001, 10002, 10021, 10022, 10023 Therefore, the role of the drug in combination with chemotherapy for the treatment of previously untreated advanced NSCLC is unclear.10021, 10022, 10023 In addition, although exploratory analyses in the FLEX and BMS-099 studies suggested that overall survival results were generally consistent across most patient subgroups, exploratory analyses of progression-free survival in the BMS-099 study suggested some differences in treatment effect in certain patient subgroups (as compared with the overall population).10001, 10002 Additional studies are needed to validate predictive tumor biomarkers and identify subgroups of patients with previously untreated advanced NSCLC who might derive clinical benefit (e.g., prolonged progression-free survival, prolonged overall survival, improved quality of life) from the addition of cetuximab to chemotherapy.10017, 10021, 10022, 10023 The AHFS Oncology Expert Committee concluded that use of cetuximab in combination with various chemotherapy regimens as first-line therapy for advanced (stage IIIB [with malignant pleural effusion] or IV [metastatic]) NSCLC currently is not fully established because of equivocal evidence.10024
Cetuximab is administered by IV infusion.1, 7 The drug should not be administered by rapid IV injection, such as IV push or bolus .1 The initial dose of cetuximab is administered over 2 hours, and the subsequent weekly dose is administered over 1 hour.1 The maximum infusion rate should not exceed 10 mg/minute.1
Cetuximab injection should be inspected visually for particulate matter and discoloration whenever solution and container permit.1 Cetuximab injection for IV infusion should be clear and colorless and may contain a small amount of easily visible, white, amorphous cetuximab particulates.1 Cetuximab injection for IV infusion should not be diluted, and vials should not be shaken.1
Cetuximab may be administered using either an infusion pump or a syringe pump.1 The drug must be administered through a low-protein-binding 0.22- µ m inline filter.1 Patients should be monitored for signs of infusion reactions during and for 1 hour following cetuximab infusion.1, 7, 10 For patients experiencing infusion reactions requiring treatment, monitoring should be continued until the event is resolved.1, 10 (See Infusion-related Effects under Warnings/Precautions: Warnings, in Cautions.)
Cetuximab solution should be stored in unopened vials under refrigeration at 2-8°C and protected from freezing.1 Preparations of cetuximab solution in infusion containers are chemically and physically stable for up to 12 hours at 2-8°C and up to 8 hours at controlled room temperature (20-25°C); any solution remaining in the infusion container after 8 hours (if stored at room temperature) or after 12 hours (if refrigerated) should be discarded.1 Cetuximab contains no preservatives; any unused portion of the vial should be discarded.1
To minimize the risk of infusion-related reactions associated with cetuximab,4 premedication with an antihistamine (e.g., 50 mg of IV diphenhydramine hydrochloride 30-60 minutes prior to the first dose of cetuximab) is recommended.1 Based on the occurrence and severity of previous infusion reactions, premedication with an antihistamine may be administered for subsequent cetuximab doses as clinically indicated.1
For the management of previously treated EGFR-expressing metastatic colorectal cancer, either as monotherapy or in combination therapy with irinotecan, an initial dose of cetuximab 400 mg/m2 is administered by IV infusion over 2 hours, followed by cetuximab 250 mg/m2 as a 1-hour IV infusion once weekly until disease progression or unacceptable toxicity occurs; the maximum infusion rate should not exceed 10 mg/minute.1, 6, 7
For use in combination with radiation therapy for the treatment of locally or regionally advanced squamous cell cancer of the head and neck, an initial dose of cetuximab 400 mg/m2 is administered by IV infusion over 2 hours at 1 week prior to the initiation of a course of radiation therapy.1 For the duration of radiation therapy (6-7 weeks), cetuximab 250 mg/m2 is administered by 1-hour IV infusion once weekly.1 Administration of cetuximab should be completed 1 hour prior to radiation therapy.1 The maximum infusion rate for cetuximab should not exceed 10 mg/minute.1 In a randomized trial for locally or regionally advanced head and neck cancer, a median of 8 doses of cetuximab was administered in patients receiving cetuximab and radiation therapy.1
For use as monotherapy for the treatment of recurrent or metastatic squamous cell cancer of the head and neck, an initial dose of cetuximab 400 mg/m2 is administered as a 2-hour IV infusion followed by cetuximab 250 mg/m2 as a 1-hour IV infusion once weekly (maximum infusion rate of 10 mg/min for initial and subsequent doses) until disease progression or unacceptable toxicity occurs.1
Dosage Modification for Toxicity and Contraindications for Continued Therapy
In patients who develop grade 1 or 2 or nonserious grade 3 or 4 infusion-related reactions, the infusion rate should be reduced by 50%.1, 6 In patients who develop serious infusion-related reactions, requiring medical intervention and/or hospitalization, cetuximab therapy should be immediately and permanently discontinued.1 (See Infusion-related Effects under Warning/Precautions: Warnings, in Cautions.)
In patients who experience severe acneiform rash, cetuximab therapy should be temporarily delayed, and subsequent doses should be reduced or therapy discontinued depending on the patient's response (see Table 1).1
Occurrence of Severe Acneiform Rash | Intervention | Outcome | Cetuximab Dosage |
|---|---|---|---|
First occurrence | Delay cetuximab infusion for 1-2 weeks | Improvement | Continue subsequent weekly dose of 250 mg/m2 |
No improvement | Discontinue cetuximab therapy | ||
Second occurrence | Delay cetuximab infusion for 1-2 weeks | Improvement | Reduce subsequent weekly dose to 200 mg/m2 |
No improvement | Discontinue cetuximab therapy | ||
Third occurrence | Delay cetuximab infusion for 1-2 weeks | Improvement | Reduce subsequent weekly dose to 150 mg/m2 |
No improvement | Discontinue cetuximab therapy | ||
Fourth occurrence | Discontinue cetuximab therapy |
If acute onset or worsening of pulmonary symptoms occurs, cetuximab therapy should be interrupted.1 If interstitial lung disease is confirmed, cetuximab therapy should be permanently discontinued.1
No special population dosage recommendations at this time.4
The manufacturer states that there are no contraindications to the use of cetuximab.1
Infusion-related effects (e.g., chills, fever, rigors, dyspnea, bronchospasm, angioedema, urticaria, hypertension, hypotension) have been reported in 15-21% of patients receiving cetuximab in clinical trials.1 Serious infusion-related effects, requiring medical intervention and immediate, permanent discontinuance of cetuximab, have included rapid airway obstruction (bronchospasm, stridor, hoarseness), hypotension, shock, loss of consciousness, myocardial infarction, and cardiac arrest.37 Severe (grade 3 or 4) infusion reactions occurred in 2-5% of 1373 patients in clinical trials; one patient died.1 Approximately 90% of severe infusion reactions occurred in association with the initial infusion of cetuximab despite premedication with antihistamines.1
Patients should be monitored for signs of infusion reactions during and for 1 hour following cetuximab infusion in a setting where resuscitation equipment and agents necessary to treat anaphylaxis are readily available.1, 7, 10 For patients experiencing infusion reactions requiring treatment, monitoring should be continued until the event is resolved.1, 10
If grade 1 or 2 or nonserious grade 3 or 4 infusion-related reactions occur, the infusion rate for cetuximab should be reduced by 50%.1 If serious infusion-related effects occur, cetuximab therapy should be immediately and permanently discontinued, and appropriate therapy (e.g., epinephrine, corticosteroids, IV antihistamines, bronchodilators, oxygen) initiated.1 Patients should be monitored until all infusion-related manifestations have completely resolved.1
Cardiopulmonary arrest and/or sudden death occurred in 4 (2%) of 208 patients receiving cetuximab and radiation therapy compared with none of 212 patients receiving radiation therapy alone for squamous cell carcinoma of the head and neck in a randomized, controlled trial.1 One patient with no history of coronary artery disease died 1 day following the last dose of cetuximab.1 Three patients with histories of coronary artery disease died at home at 27, 32, and 43 days following the last dose of cetuximab; myocardial infarction was the presumed cause of death.1 One of these patients had arrhythmia and one patient had congestive heart failure.1
Cetuximab and radiation therapy for the treatment of head and neck cancer should be used with caution in patients with a history of coronary artery disease, congestive heart failure, or arrhythmias.1 Serum concentrations of electrolytes, including magnesium, potassium, and calcium, should be monitored closely during and following cetuximab therapy.1
Adverse cardiac events—myocardial infarction in one patient and arrhythmia, diminished cardiac output, and hypotension in another patient—caused discontinuation of treatment in patients with head and neck cancer receiving cetuximab with cisplatin and radiation therapy in a clinical trial.1 The safety of cetuximab in combination with cisplatin and radiation therapy has not been established.1
Interstitial lung disease, interstitial pneumonitis (fatal in one case), and exacerbation of preexisting fibrotic lung disease have been reported in patients receiving cetuximab alone or in combination with other antineoplastic agents (e.g., cisplatin, irinotecan).1, 4, 6 Interruption or discontinuance of cetuximab therapy may be required in patients with pulmonary symptoms.1 (See Pulmonary Toxicity under Dosage Modification for Toxicity and Contraindications for Continued Therapy, in Dosage and Administration.)
Electrolyte abnormalities, sometimes severe, including hypomagnesemia, hypocalcemia, and hypokalemia, have occurred in patients receiving cetuximab.1 Hypomagnesemia occurred in 199 (55%) of 365 patients receiving cetuximab in clinical trials and was severe (grade 3 or 4) in 6-17% of patients.1 The onset of hypomagnesemia and accompanying electrolyte abnormalities may occur from days to months following initiation of cetuximab therapy.1, 10 Manifestations of hypomagnesemia may include fatigue and hypocalcemia.23 Patients should be monitored for hypomagnesemia, hypocalcemia, and hypokalemia during and for at least 8 weeks following completion of cetuximab therapy.1 Electrolyte repletion therapy should be administered as necessary and, in severe cases, intravenous replacement therapy is required.1, 10, 23
Acneiform rash occurred in 76-88% of 1373 patients receiving cetuximab in clinical trials and was severe in 1-17% of patients.1 Acneiform rash generally appears within the first 2 weeks of cetuximab therapy and may resolve following discontinuance of cetuximab; however, manifestations have persisted beyond 28 days in nearly 50% of cases.1
Other adverse dermatologic effects, including skin drying/fissuring, paronychial inflammation, infectious sequelae (e.g., abscess formation, blepharitis, conjunctivitis, keratitis, cheilitis, cellulitis, Staphylococcus aureus sepsis), and hypertrichosis also have been reported.1 Fatal toxic epidermal necrolysis has been reported in a patient receiving cetuximab for colorectal cancer.27 Abnormal hair growth has been reported in a patient receiving cetuximab for head and neck cancer.24
Reduction of dosage or discontinuance of therapy is required in patients who develop severe acneiform rash.1 (See Dermatologic Toxicity under Dosage Modification for Toxicity and Contraindications for Continued Therapy, in Dosage and Administration.)
Other serious adverse effects associated with cetuximab include radiation dermatitis, sepsis, renal failure, and pulmonary embolus.1 Sepsis occurred in 1-4% of patients receiving cetuximab.1 Renal failure was reported in 1% of patients receiving cetuximab for colorectal cancer.1 Across all studies, cetuximab therapy was discontinued in 3-10% of patients because of adverse effects.1 (See Warnings under Cautions: Warnings/Precautions.)
In clinical trials for colorectal cancer, testing for evidence of EGFR expression was required.1 However, some authorities state that routine EGFR expression testing is not recommended in patients with colorectal cancer and that patients should not be included or excluded from cetuximab therapy based solely on EGFR test results.31
Because expression of EGFR has been detected in nearly all head and neck cancers, EGFR testing was not required in these clinical trials.1
Patients receiving cetuximab should be monitored for dermatologic toxicity and infectious sequelae.1
Patients should be monitored periodically for hypomagnesemia, and accompanying hypocalcemia and hypokalemia, during and following the completion of cetuximab therapy.1, 10 Monitoring should be continued for at least 8 weeks following completion of therapy.1, 10
Non-neutralizing anticetuximab antibodies were detected in about 5% of patients (49/1001) receiving cetuximab; although the incidence of antibody development to cetuximab has not been fully established, there appears to be no effect on the safety and efficacy of the drug.1
Category C.1 (See Users Guide.)
It is not known whether cetuximab is distributed into milk; however, human immunoglobulin G1 (IgG1) is distributed into milk.1 Because of the potential for distribution of IgG antibodies such as cetuximab into milk and the risks for serious adverse reactions from cetuximab in nursing infants, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman.1 Based on the long half-life of cetuximab, women should be advised to discontinue nursing while receiving cetuximab therapy and for at least 60 days following the last dose of the drug (see Description).1
Safety and efficacy of cetuximab have not been established in pediatric patients.1
Approximately 34% of the 1062 patients receiving cetuximab (alone or in combination with irinotecan) in clinical studies for advanced colorectal cancer were 65 years of age or older.1 No overall differences in safety and efficacy relative to younger adults were observed.1
Clinical studies of cetuximab for head and neck cancer did not include sufficient numbers of patients 65 years of age and older to determine whether geriatric patients respond differently than younger patients.1 Of 208 patients with advanced head and neck cancer receiving cetuximab and radiation therapy in a clinical trial, 45 patients (22%) were 65 years of age or older.1
The most common adverse effects, observed in at least 25% of patients receiving cetuximab, are adverse dermatologic effects (including rash, pruritus, and nail changes), headache, diarrhea, and infection.1 Across studies, infection occurred in 13-35% of patients receiving cetuximab.1
The most common adverse effects in patients receiving cetuximab in combination with irinotecan for advanced colorectal cancer include acneiform rash (88%), asthenia/malaise (73%), diarrhea (72%), and nausea (55%); the most common grade 3 or 4 adverse effects include diarrhea (22%), leukopenia (17%), asthenia/malaise (16%), and acneiform rash (14%).1
The most common adverse effects in patients receiving cetuximab and best supportive care for advanced colorectal cancer include rash/desquamation (89%), fatigue (89%), abdominal pain (59%), pain (51%), dry skin (49%), dyspnea (48%), and constipation (46%).1
The most common adverse effects in patients receiving cetuximab in combination with radiation therapy for advanced head and neck cancer include acneiform rash (87%); radiation dermatitis (86%); weight loss (84%); asthenia (56%); nausea (49%); and elevated serum ALT (43%), AST (38%), and alkaline phosphatase concentrations (33%).1
Pharmacokinetic interaction with irinotecan unlikely.1
Potential pharmacologic interaction (death, cardiotoxicity, increased risk of adverse dermatologic effects).1 Death and serious cardiotoxicity occurred in patients with locally advanced squamous cell head and neck cancer receiving cetuximab, cisplatin, and radiation therapy.1 Rash was reported in 87% of patients with locally advanced squamous cell head and neck cancer who received cetuximab concomitantly with radiation therapy.1 The incidence of late radiation toxicities was higher in patients receiving cetuximab and radiation therapy than in those receiving radiation therapy alone.1
Cetuximab, a recombinant chimeric (human-murine) monoclonal antibody, is an antineoplastic agent.1, 6, 7 The drug is an immunoglobulin containing human framework (i.e., IgG1 heavy and kappa light constant regions) and murine Fv regions.1
Cetuximab binds specifically to the extracellular domain of the human epidermal growth factor receptor (EGFR, HER1, c-erbB-1) on both normal and tumor cells and competitively blocks the cellular action of EGF and other ligands (e.g., transforming growth factor [TGF]-α).1, 6, 35 EGFR is a transmembrane glycoprotein that belongs to the subfamily of type I receptor tyrosine kinases, which includes EGFR (HER1), HER2, HER3, and HER4.1, 35 While EGFR is expressed in many normal epithelial tissues (e.g., skin, hair follicle), overexpression of the glycoprotein is detected in human carcinomas (e.g., colon, rectum, head and neck).1, 6, 35 In vitro assays and in vivo animal studies have shown that binding of cetuximab to EGFR blocks phosphorylation and activation of receptor-associated kinases; this results in inhibition of cell growth, induction of apoptosis (programmed cell death), and decreased matrix metalloproteinase and vascular endothelial growth factor production.1, 6, 35 Signal transduction through EGFR leads to activation of the wild-type (nonmutated) KRAS gene.35, 36, 37 However, the presence of an activating somatic mutation of the KRAS gene (mutated KRAS ) in a cancer cell can lead to dysregulation of signaling pathways and resistance to EGFR inhibitor therapy (e.g., cetuximab, panitumumab).35, 36, 37 In vitro, cetuximab can mediate antibody-dependent cellular cytotoxicity against certain types of human tumors.1
In vitro tests and in vivo animal studies have suggested that cetuximab inhibits growth and survival of tumor cells that express EGFR,1 while such antitumor effects were not observed in human cancer xenografts that lacked EGFR expression.1 In xenograft models for human tumors in mice, addition of cetuximab to radiation therapy or irinotecan resulted in an increased antitumor effect when compared with radiation therapy or chemotherapy alone.1
The pharmacokinetic disposition of cetuximab was similar in patients receiving the drug for head and neck cancer or colorectal cancer.1 Following administration of the recommended regimen of cetuximab (initial dose, followed by subsequent weekly doses), steady-state cetuximab concentrations are achieved by the third weekly infusion; the mean half-life of cetuximab following multiple dosing is approximately 112 hours.1, 6 The major route of clearance from the circulation is believed to be through internalization of the cetuximab EGFR complex on hepatocytes and skin.7
Risk of infusion-related effects and adverse pulmonary and dermatologic effects.1 Advise patients to report signs or symptoms of infusion reactions, such as fever, chills, or breathing problems.1
Importance of advising patients to use sunscreen and hats and limit sun exposure during and for 2 months following discontinuance of cetuximab therapy to avoid exacerbation of adverse dermatologic effects.1
Necessity of advising men and women to use an effective method of contraception during and for 6 months following the last dose of cetuximab therapy.1 Advise pregnant women of risk to the fetus.1 Advise women to avoid breast-feeding during and for 2 months following the last dose of cetuximab.1
Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.1
Additional Information
Overview (see Users Guide). For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.
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.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Parenteral | Injection, for IV infusion only | 2 mg/mL (100 and 200 mg) |
1. Bristol-Myers Squibb. Erbitux® (cetuximab) prescribing information. Princeton, NJ: 2008 Nov.
2. Saltz LB, Meropol NJ, Loehrer PJ et al. Phase II trial of cetuximab in patients with refractory colorectal cancer that expresses the epidermal growth factor receptor. J Clin Oncol . 2004; 22:1201-8. [PubMed 14993230]
3. Cunningham D, Humblet Y, Siena S et al. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med . 2004; 351:337-45. [PubMed 15269313]
4. Bristol-Myers Squibb, Princeton, NJ: Personal communication.
5. Burtness B, Goldwasser MA, Flood W et al. Phase III randomized trial of cisplatin plus placebo compared with cisplatin plus cetuximab in metastatic/recurrent head and neck cancer: an Eastern Cooperative Oncology Group study. J Clin Oncol . 2005; 23:8646-54. [PubMed 16314626]
6. Anon. Two new drugs for colon cancer. Med Lett Drugs Ther. 2004; 46:46-7.
7. Reynolds NA, Wagstaff AJ. Cetuximab: in the treatment of metastatic colorectal cancer. Drugs . 2004; 64:109-18. [PubMed 14723561]
8. Food and Drug Administration. Orphan designations pursuant to Section 526 of the Federal Food and Cosmetic Act as amended by the Orphan Drug Act (P.L. 97-414). Rockville, MD; 2004 Sep 16. From FDA web site. [Web]
9. Bonner JA, Harari PM, Giralt J et al. Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med . 2006; 354:567-78. [PubMed 16467544]
10. Rowinsky EK, Smyth AC. Dear healthcare provider letter regarding important drug warning for Erbitux® (cetuximab). ImClone Systems and Bristol Myers Squibb; 2005 Sep 13.
11. Anon. Drugs of choice for cancer. Treat Guidel Med Lett . 2003; 1:41-52. [PubMed 15529105]
12. Vermorken JB, Trigo J, Hitt R et al. Open-label, uncontrolled, multicenter phase II study to evaluate the efficacy and toxicity of cetuximab as a single agent in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck who failed to respond to platinum-based therapy. J Clin Oncol . 2007; 25:2171-7. [PubMed 17538161]
13. Posner MR, Wirth LJ. Cetuximab and radiotherapy for head and neck cancer. N Engl J Med . 2006; 354:634-6. [PubMed 16467552]
14. Baselga J, Trigo JM, Bourhis J et al. Phase II multicenter study of the antiepidermal growth factor receptor monoclonal antibody cetuximab in combination with platinum-based chemotherapy in patients with platinum-refractory metastatic and/or recurrent squamous cell carcinoma of the head and neck. J Clin Oncol . 2005; 23:5568-77. [PubMed 16009950]
15. Herbst RS, Arquette M, Shin DM et al. Phase II multicenter study of the epidermal growth factor receptor antibody cetuximab and cisplatin for recurrent and refractory squamous cell carcinoma of the head and neck. J Clin Oncol . 2005; 23:5578-87. [PubMed 16009949]
16. Vermorken JB, Mesia R, Rivera F et al. Platinum-based chemotherapy plus cetuximab in head and neck cancer. N Engl J Med . 2008; 359:1116-27. [PubMed 18784101]
17. Pfister DG, Su YB, Kraus DH et al. Concurrent cetuximab, cisplatin, and concomitant boost radiotherapy for locoregionally advanced, squamous cell head and neck cancer: a pilot phase II study of a new combined-modality paradigm. J Clin Oncol . 2006; 24:1072-8. [PubMed 16505426]
18. Ang KK, protocol chair. Phase III randomized study of concurrent accelerated fractionated radiotherapy and cisplatin with versus without cetuximab in patients with stage III or IV squamous cell carcinoma of the oropharynx, hypopharynx, or larynx. Protocol ID: RTOG-0522. Last modified: 8/24/2006. National Cancer Institute: Clinical Trials (database).
19. Saltz L, Rubin M, Hochster H et al. Cetuximab (IMC-C225) plus irinotecan (CPT-11) is active in CPT-11-refractory colorectal cancer (CRC) that expresses epidermal growth factor receptor (EGFR). Proc ASCO . 2001; Abstract No. 7.
20. Venook A, Niedzwiecki D, Hollis D et al. Phase III study of irinotecan/5FU/LV (FOLFIRI) or oxaliplatin/5FU/LV (FOLFOX) ± cetuximab for patients (pts) with untreated metastatic adenocarcinoma of the colon or rectum (MCRC): CALGB 80203 preliminary results. Proc ASCO . 2006; Abstract No. 3509.
21. Venook A, protocol chair. Phase III randomized study of cetuximab and/or bevacizumab in combination with either oxaliplatin, fluorouracil, and leucovorin calcium (FOLFOX) or irinotecan hydrochloride, fluorouracil, and leucovorin calcium (FOLFIRI) in patients with previously untreated metastatic adenocarcinoma of the colon or rectum. Protocol ID: CALGB-C80405. Last modified: 8/24/2006. National Cancer Institute: Clinical Trials (database).
22. Chung KY, Shia J, Kemeny NE et al. Cetuximab shows activity in colorectal cancer patients with tumors that do not express the epidermal growth factor receptor by immunohistochemistry. J Clin Oncol . 2005; 23:1803-10. [PubMed 15677699]
23. Schrag D, Chung KY, Flombaum C et al. Cetuximab therapy and symptomatic hypomagnesemia. J Natl Cancer Inst . 2005; 97:1221-4. [PubMed 16106027]
24. Montagut C, Grau JJ, Grimalt R et al. Abnormal hair growth in a patient with head and neck cancer treated with the anti-epidermal growth factor receptor monoclonal antibody cetuximab. J Clin Oncol . 2005; 23:5273-5. [PubMed 16051981]
25. Jonker DJ, O'Callaghan CJ, Karapetis CS et al. Cetuximab for the treatment of colorectal cancer. N Engl J Med . 2007; 357:2040-8. [PubMed 18003960]
26. Lièvre A, Bachet JB, Boige V et al. KRAS mutations as an independent prognostic factor in patients with advanced colorectal cancer treated with cetuximab. J Clin Oncol . 2008; 26:374-9.
27. Lin WL, Lin WC, Yang JY et al. Fatal toxic epidermal necrolysis associated with cetuximab in a patient with colon cancer. J Clin Oncol . 2008; 26:2779-80. [PubMed 18509187]
28. Allegra CJ, Jessup JM, Somerfield MR et al. American Society of Clinical Oncology provisional clinical opinion: testing for KRAS gene mutations in patients with metastatic colorectal carcinoma to predict response to anti-epidermal growth factor receptor monoclonal antibody therapy. J Clin Oncol . 2009; 27:2091-6. [PubMed 19188670]
29. Cunningham D, Humblet Y, Siena S et al. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med . 2004; 351:337-45. [PubMed 15269313]
30. Italiano A, Follana P, Caroli FX et al. Cetuximab shows activity in colorectal cancer patients with tumors for which FISH analysis does not detect an increase in EGFR gene copy number. Ann Surg Oncol . 2008; 15:649-54. [PubMed 17987340]
31. National Comprehensive Cancer Network (NCCN). Clinical practice guidelines in oncology; colon cancer. Version 2.2009. Accessed from the NCCN website. [Web]
33. Van Cutsem E, Lang I, Moiseyenko V et al. KRAS status and efficacy in the first-line treatment of patients with metastatic colorectal cancer (mCRC) treated with FOLFIRI with or without cetuximab: the CRYSTAL experience. Proceedings of the 44th Annual Meeting of ASCO, Chicago, IL, 2008 May 30-Jun 3. Abstr. No. 2.
34. Bokemeyer C, Bondarenko I, Hartmann JT et al. KRAS status and efficacy of first-line treatment of patients with metastatic colorectal cancer (mCRC) with FOLFOX with or without cetuximab: the OPUS experience. Proceedings of the 44th Annual Meeting of ASCO, Chicago, IL 2008 May 30-Jun 3. Abstr. No. 4000.
35. Chang DZ, Kumar V, Ma Y et al. Individualized therapies in colorectal cancer: KRAS as a marker for response to EGFR-targeted therapy. J Hematol Oncol . 2009; 2:18. [PubMedCentral][PubMed 19386128]
36. Normanno N, Tejpar S, Morgillo F et al. Implications for KRAS status and EGFR-targeted therapies in metastatic CRC. Nat Rev Clin Oncol . 2009; 6:519-27. [PubMed 19636327]
37. Bristol-Myers Squibb. Erbitux® (cetuximab) solution for intravenous infusion prescribing information. Princeton, NJ: 2009 Jul.
38. Freeman DJ, Juan T, Reiner M et al. Association of K-ras mutational status and clinical outcomes in patients with metastatic colorectal cancer receiving panitumumab alone. Clin Colorectal Cancer . 2008; 7:184-90. [PubMed 18621636]
39. Santini D, Loupakis F, Vincenzi B et al. High concordance of KRAS status between primary colorectal tumors and related metastatic sites: implications for clinical practice. Oncologist . 2008; 13:1270-5. [PubMed 19056857]
40. Di Nicolantonio F, Martini M, Molinari F et al. Wild-type BRAF is required for response to panitumumab or cetuximab in metastatic colorectal cancer. J Clin Oncol . 2008; 26:5705-12. [PubMed 19001320]
41. Peeters M, Balfour J, Arnold D. Review article: panitumumab--a fully human anti-EGFR monoclonal antibody for treatment of metastatic colorectal cancer. Aliment Pharmacol Ther . 2008; 28:269-81. [PubMed 19086328]
42. Weber J, McCormack PL. Panitumumab in metastatic colorectal cancer with wild-type KRAS . BioDrugs . 2008; 22:403-11. [PubMed 18998757]
43. Amado RG, Wolf M, Peeters M et al. Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. J Clin Oncol . 2008; 26:1626-34. [PubMed 18316791]
10001. Pirker R, Pereira JR, Szczesna A et al. Cetuximab plus chemotherapy in patients with advanced non-small-cell lung cancer (FLEX): an open-label randomised phase III trial. Lancet . 2009; 373:1525-31. [PubMed 19410716]
10002. Lynch TJ, Patel T, Dreisbach L et al. Cetuximab and first-line taxane/carboplatin chemotherapy in advanced non-small-cell lung cancer: results of the randomized multicenter phase III trial BMS099. J Clin Oncol . 2010; 28:911-7. [PubMed 20100966]
10004. Herbst RS, Kelly K, Chansky K et al. Phase II selection design trial of concurrent chemotherapy and cetuximab versus chemotherapy followed by cetuximab in advanced-stage non-small-cell lung cancer: Southwest Oncology Group study S0342. J Clin Oncol . 2010; 28:4747-54. [PubMedCentral][PubMed 20921467]
10005. Hirsch FR, Herbst RS, Olsen C, et al. Increased EGFR gene copy number detected by fluorescent in situ hybridization predicts outcome in non-small cell lung cancer patients treated with cetuximab and chemotherapy. J Clin Oncol. 2008; 26:3351-57.
10006. Butts CA, Bodkin D, Middleman ELet al. Randomized phase II study of gemcitabine plus cisplatin, with or without cetuximab, as first-line therapy for patients with advanced or metastatic non-small cell lung cancer. J Clin Oncol. 2007; 25:5777-84. [PubMed 18089875]
10007. Ettinger DS. Clinical implications of EGFR expression in the development and progression of solid tumors: focus on non-small cell lung cancer. The Oncologist. 2006; 11:358-73. [PubMed 16614231]
10008. Sequist LV, Bell DW, Lynch TL et al. Molecular predictors of response to epidermal growth factor receptor antagonists in non-small cell lung cancer. J Clin Oncol. 2007; 25:587-95. [PubMed 17290067]
10009. Hanna S, Lilenbaum R, Ansari R et al. Phase II trial of cetuximab in patients with previously treated non-small cell lung cancer. J Clin Oncol. 2006; 24:5253-5257. [PubMed 17114658]
10010. Ciardiello F and Tortora G. EGFR antagonists in cancer treatment. N Engl J Med. 2008; 358:1160-74. [PubMed 18337605]
10011. AHFS Oncology Expert Committee reviewers' comments (personal observations).
10012. Schiller JH, Harrington D, Belani C et al. Comparison of four chemotherapy regimens for advanced non-small cell lung cancer. N Engl J Med. 2002; 346: 92-8. [PubMed 11784875]
10013. Socinski MA, Crowell R, Hensing TE, et al. Treatment of non-small cell lung cancer, stage IV: ACCP evidence-based clinical practice guidelines (2nd edition). Chest. 2007;132:277-289.
10014. Sandler A Gray R, Perry M et al. Paclitaxel-carboplatin alone or with bevacizumab for non-small cell lung cancer. N Engl J Med. 2006; 355:2542-50. [PubMed 17167137]
10015. Chung KI, Shia J, Kemeny N et al. Cetuximab shows activity in colorectal cancer patients with tumors that do not express the epidermal growth factor receptor by immunohistochemistry. J Clin Oncol. 2005; 23:1803-10. [PubMed 15677699]
10016. O'Byrne KJ, Gatzemeier U, Bondarenko I et al. Molecular biomarkers in non-small-cell lung cancer: a retrospective analysis of data from the phase 3 FLEX study. Lancet Oncol . 2011; 12:795-805. [PubMed 21782507]
10017. Khambata-Ford S, Harbison CT, Hart LL et al. Analysis of potential predictive markers of cetuximab benefit in BMS099, a phase III study of cetuximab and first-line taxane/carboplatin in advanced non-small-cell lung cancer. J Clin Oncol . 2010; 28:918-27. [PubMed 20100958]
10018. Pirker R, Pereira JR, von Pawel J et al. EGFR expression as a predictor of survival for first-line chemotherapy plus cetuximab in patients with advanced non-small-cell lung cancer: analysis of data from the phase 3 FLEX study. Lancet Oncol . 2012; 13:33-42. [PubMed 22056021]
10019. Rosell R, Robinet G, Szczesna A et al. Randomized phase II study of cetuximab plus cisplatin/vinorelbine compared with cisplatin/vinorelbine alone as first-line therapy in EGFR-expressing advanced non-small-cell lung cancer. Ann Oncol . 2008; 19:362-9. [PubMed 17947225]
10021. Redman MW, Crowley JJ, Herbst RS et al. Design of a phase III clinical trial with prospective biomarker validation: SWOG S0819. Clin Cancer Res . 2012; 18:4004-12. [PubMedCentral][PubMed 22592956]
10022. Socinski MA, Evans T, Gettinger S et al. Treatment of stage IV non-small cell lung cancer: Diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest . 2013; 143(5 Suppl):e341S-68S. [PubMedCentral][PubMed 23649446]
10023. European Medicines Agency. Withdrawal assessment report: Erbitux (cetuximab). Procedure No.: EMEA/H/C/000558/II/0043. 2012 Apr 19. From EMA website. [Web]
10024. AHFS Final Determination of Medical Acceptance: Off-label use of cetuximab in combination with chemotherapy for the first-line treatment of advanced non-small cell lung cancer. Published April 2015.