Cetuximab

Class: Antineoplastic Agents
VA Class: AN900
Chemical Name: Disulfide with human-mouse monoclonal C225 κ-chain anti-(human epidermal growth factor receptor) (human-mouse monoclonal C225 γ1-chain) immunoglobulin G1 dimer
CAS Number: 205923-56-4
Brands: Erbitux

• Infusion-related Effects


• 
  

  Severe infusion-related effects (rarely fatal) reported in about 3% of patients.^{1 6} May occur after any dose; however, approximately 90% of reported cases occurred during first infusion despite premedication with antihistamines.¹

  
  


• 
  

  Manifested as rapid airway obstruction (bronchospasm, stridor, hoarseness), urticaria, hypotension, and/or cardiac arrest.^{1 6}

  
  


• 
  

  Monitor patients during and for 1 hour following each infusion.⁷ If severe infusion-related effects occur, discontinue cetuximab immediately and permanently.¹ (See Infusion-related Effects under Cautions.)

  
  

• Cardiopulmonary Arrest


• 
  

  Cardiopulmonary arrest and/or sudden death reported in 2% of patients with squamous cell carcinoma of the head and neck receiving cetuximab in combination with radiation therapy in one study.¹ (See Cardiopulmonary Arrest under Cautions.) Fatal events occurred within 1–43 days after last cetuximab dose.¹ Etiology of these events is unknown.¹

  
  


• 
  

  Caution in patients with head and neck cancer who have history or clinical evidence of CAD, CHF, or arrhythmias.¹ Closely monitor serum electrolytes (including magnesium, potassium, and calcium) during and after cetuximab therapy.¹

  
  

Introduction

Antineoplastic agent; a recombinant chimeric (human-murine) monoclonal antibody that binds to epidermal growth factor receptors (EGFR).^{1 6 7}

Uses for Cetuximab

Head and Neck Cancer

Used in combination with radiation therapy for the treatment of locally or regionally advanced squamous cell carcinoma of the head and neck, particularly in patients who cannot tolerate platinum-based chemotherapy with radiation therapy (designated an orphan drug by FDA for this use).^{8 1 13} Platinum-based chemotherapy with radiation therapy is current standard of care for treatment of advanced head and neck cancer.¹³

Used as a single agent for the treatment of recurrent or metastatic squamous cell carcinoma of the head and neck that is refractory to platinum-based chemotherapy (designated an orphan drug by FDA for this use).^{1 8 12}

Under investigation for use in combination with other antineoplastic agents (e.g., cisplatin), with or without radiation therapy,† for the treatment of recurrent or metastatic squamous cell carcinoma of the head and neck.^{5 14 15 16 17 18}

Colorectal Cancer

Used in combination with irinotecan for the treatment of metastatic colorectal cancer that is refractory to irinotecan-based chemotherapy in patients with tumors that express EGFR.^{1 2 3 19}

Also 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}

Efficacy determined based on objective response rates; actual clinical benefits (e.g., improvement in disease-related symptoms, increased survival) not adequately studied.¹

Under investigation for use in combination with chemotherapy regimens (e.g., irinotecan/fluorouracil/leucovorin [FOLFIRI], oxaliplatin/fluorouracil/leucovorin [FOLFOX]) for the first-line† treatment of metastatic colorectal cancer.^{20 21}

Other Uses

For information on the use of cetuximab for non-small cell lung cancer†, see AHFS Oncology Final Determinations at .

AHFS Off-label Use Determinations for Oncology

Off-label Use (condition and patient population)	Regimen	Strength of Evidence; Strength of Study End Point(s)	Grade of Recommendation	Disclosure Information	AHFS Publication Date
First-line therapy for stage IIIB (with malignant pleural effusion) and stage IV non-small cell lung cancer	Cetuximab 400 mg/m2 (week 1) IV followed by 250 mg/m2 weekly, plus Cisplatin 80 mg/m2 IV infusion day 1 and Vinorelbine 25 mg/m2 as an IV injection on days 1 and 8. Cycle with cisplatin and vinorelbine repeats every 3 weeks for a total of 6 cycles, then cetuximab continued as maintenance therapy.10001	Moderate quality; Overall survival	Reasonable choice for patients with confirmed EGFR expressing NSCLC who are not candidates to receive a bevacizumab containing regimen (Accepted)	No conflicts of interest were disclosed during this review.	October 2008
First-line therapy for stage IIIB (with malignant pleural effusion) and stage IV non-small cell lung cancer	Carboplatin (dose calculated to yield a target AUC of 6) by IV infusion on day 1 Paclitaxel 225 mg/m2 IV infusion on day 1 Cycle of carboplatin and paclitaxel repeats every 3 weeks for a total of 4 cycles (SWOG 0342 study)10004 10005 or for a maximum of 6 cycles (BMS 099)10002 10003 BMS 099: Cetuximab 400 mg/m2 (week 1), followed by 250 mg/m2 weekly until disease progression10002 SWOG 0342: Cetuximab administered at same dosage either concurrently with or sequentially after carboplatin/paclitaxel therapy.	Moderate quality; Overall survival (BMS 099) Moderate quality; Overall survival (SWOG 0342)	Not fully established	No conflicts of interest were disclosed during this review.	October 2008
First-line therapy for stage IIIB (with malignant pleural effusion) and stage IV non-small cell lung cancer	Cetuximab 400 mg/m2 (day 1 of week 1) IV, followed by 250 mg/m2 weekly.10002 Carboplatin (dose calculated to yield a target AUC of 6) by IV infusion on day 1 Docetaxel 75 mg/m2 IV infusion on day 1 Cycle with carboplatin and docetaxel repeats every 3 weeks for a total of 6 cycles, then cetuximab continued as maintenance therapy.	Moderate quality; Overall survival	Not fully established	No conflicts of interest were disclosed during this review.	October 2008
First-line therapy for stage IIIB (with malignant pleural effusion) and stage IV non-small cell lung cancer	Cetuximab 400 mg/m2 (week 1) IV administered as a 2-hour infusion, followed by 250 mg/m2 weekly administered as an 1-hour infusion10006 Cisplatin 75 mg/m2 IV infusion on day 1 Gemcitabine 1250 mg/m2 IV infusion on day 1 and day 8 Cycle with cisplatin and gemcitabine repeats every 3 weeks for a maximum of 6 cycles, then cetuximab continued as maintenance therapy.	Low quality; Overall survival	Not fully established	No conflicts of interest were disclosed during this review.	October 2008
First-line therapy for stage IIIB (with malignant pleural effusion) and stage IV non-small cell lung cancer	Cetuximab 400 mg/m2 (week 1) IV administered as a 2-hour infusion, followed by 250 mg/m2 weekly administered as an 1-hour infusion10006 Carboplatin (dose calculated to yield a target AUC of 5) by IV infusion on day 1 Gemcitabine 1000 mg/m2 IV infusion on day 1 and day 8 Cycle with carboplatin and gemcitabine repeats every 3 weeks for a maximum of 6 cycles, then cetuximab continued as maintenance therapy until disease progression	Low quality; Overall survival	Not fully established	No conflicts of interest were disclosed during this review	October 2008

Clinical Trial Summary

Cetuximab with Vinorelbine and Cisplatin

The FLEX study is a phase 3, multicenter, randomized study (n=1125) comparing the regimen of cetuximab, vinorelbine, and cisplatin with vinorelbine and cisplatin without concurrent cetuximab as primary treatment for stage IIIB (with a malignant pleural effusion) and stage IV non-small cell lung cancer (NSCLC) patients.¹⁰⁰⁰¹ All patients’ cancers were confirmed by immunohistochemistry (IHC) to be expressing the epidermal growth factor receptor protein (EGFR-positive); patients with an ECOG performance status (PS) of 0–2 were included.¹⁰⁰⁰¹ All NSCLC histologies were included.¹⁰⁰⁰¹

The primary end point was overall survival, with secondary objectives of response rate, progression-free survival, disease control, quality of life, and safety. The study was powered to detect a difference in overall survival (OS) based on a hazard ratio (HR) of 0.8.¹⁰⁰⁰¹

The OS was 10.1 and 11.3 months (HR: 0.87, 95% CI= 0.762-0.996 [p=0.044]) and the 1-year survival rate was 42 and 47% for the chemotherapy alone and chemotherapy plus cetuximab arms, respectively.¹⁰⁰⁰¹

The response rates were 29 and 36% for chemotherapy alone versus the cetuximab-containing regimen, respectively; the progression-free survival was identical for both groups (4.8 months) while time-to-treatment failure was 4.2 and 3.7 months for the cetuximab-containing regimen and the chemotherapy-alone regimen, respectively. (p=0.0015)¹⁰⁰⁰¹

A subgroup analysis revealed a higher OS in patients in the Asian subgroup compared with the Caucasian cohort (19.5 versus 9.6 months, respectively). A higher percentage (61 versus 17%) of the Asian subgroup received a tyrosine-kinase inhibitor (TKI) at the time of relapse following their initial study regimen.¹⁰⁰⁰¹ For the Caucasian patients (84%), the OS was 10.5 and 9.1 months, with 1-year survival rates of 45 and 37% (HR: 0.8; 95% CI = 0.694-0.928 [p=0.003]) for the cetuximab-containing and chemotherapy alone arms, respectively.¹⁰⁰⁰¹

The incidence of febrile neutropenia was high in both treatment arms, with a slightly higher incidence (22 versus 15%) in the cetuximab-containing arm relative to the chemotherapy-alone arm.¹⁰⁰⁰¹ Grade 3 acneiform rash was reported at an incidence of 10% in the cetuximab arm compared with less than 1% in the chemotherapy-alone arm.¹⁰⁰⁰¹

Additional post-study treatment was given to 54 and 61% of the patients at the time of progression for the cetuximab-containing and chemotherapy-alone arms, respectively.¹⁰⁰⁰¹ The use of radiation therapy and chemotherapy was similar in both groups; however, TKI therapy was used more frequently (27 vs 17%) in the chemotherapy-alone arm.¹⁰⁰⁰¹

The efficacy results were reported based on an intent-to-treat analysis; however, the OS failed to meet the study objective with a reported HR of 0.87 compared with the presumptive HR of 0.8.¹⁰⁰⁰¹

EGFR and KRAS mutation status is not known for this patient population; there are no plans to collect these data for this study.

Cetuximab with Carboplatin and Paclitaxel (or Docetaxel)

BMS 099 is a phase 3 randomized study (n=676) comparing the regimen of cetuximab, carboplatin, and a taxane (docetaxel or paclitaxel, selected by the investigator for the individual patient) with carboplatin and a taxane without cetuximab as primary treatment for stage IIIB (with a malignant pleural effusion) and stage IV NSCLC.^{10002 10003} No EGFR testing was required for enrollment in the study.¹⁰⁰⁰² All patients had an ECOG performance status of 0–1.¹⁰⁰⁰² All NSCLC histologies were included.¹⁰⁰⁰²

The primary end point was progression-free survival (PFS), assessed by the Independent Radiologic Review Committee (IRRC); the secondary end points were response rate (assessed by IRRC and the investigators), overall survival, quality of life, safety, and PFS (assessed by the investigators).¹⁰⁰⁰² The study was powered to determine an improvement in PFS based on an HR of 0.75.¹⁰⁰⁰²

PFS was slightly prolonged with the cetuximab arm compared with the carboplatin-taxane arm (4.4 versus 4.24 months, respectively) (HR: 0.9, 95% CI= 0.761-1.069 [p=0.23]); the objective response rate also was slightly higher for the cetuximab arm compared with carboplatin plus a taxane (25.7 versus 17.2%, respectively).¹⁰⁰⁰² Both assessments reflect the analysis performed by the blinded Independent Radiologic Review Committee (IRRC).¹⁰⁰⁰²

The overall survival was improved (but not a statistically significant improvement) for the cetuximab-containing arm compared with the carboplatin-taxane arm (9.7 versus 8.4 months, respectively) (HR: 0.89, 95% CI=0.75-1.05 [p=0.17]).¹⁰⁰⁰³

The incidence of febrile neutropenia was similar between both groups (i.e., less than 5%).¹⁰⁰⁰²

The study failed to meet its study objective of an improvement in PFS with a HR of 0.89 compared with the presumptive HR of 0.8.¹⁰⁰⁰²

The investigators plan to perform EGFR testing using gene copy detection by FISH; analysis of both the presence and impact of either an EGFR and/or a KRAS mutation on response will be evaluated.¹⁰⁰⁰²

A second study, SWOG 0342, is a phase 2 randomized trial (n= 242) comparing carboplatin and paclitaxel plus concurrent cetuximab therapy with a sequential regimen of carboplatin and paclitaxel followed by cetuximab therapy as first-line therapy for stage IIIB (with malignant pleural effusion) and stage IV NSCLC.^{10004 10005} EGFR testing was not required for enrollment in the study; however, one-third of the patients consented to having EGFR testing performed using gene copy number by FISH.¹⁰⁰⁰⁵ All patients had an ECOG performance status of 0–1. All NSCLC histologies were included.¹⁰⁰⁰⁴

The primary end point was overall survival.^{10004 10005} The study was powered to show a difference of 30% between groups based on an HR of 1.3.¹⁰⁰⁰⁴

The median overall survival was slightly higher with the concurrent versus the sequential regimen (11 versus 10 months, respectively).¹⁰⁰⁰⁴ The PFS was identical at 4 months for both groups, and the objective response rate was similar for the concurrent and sequential groups (34 versus 31%, respectively).¹⁰⁰⁰⁴

The incidence of grade 3 and 4 febrile neutropenia was low for both regimens; however, a statistically significant increase was reported with the concurrent arm relative to the sequential arm (5 versus 1%, respectively; p=0.04).¹⁰⁰⁰⁴ Reports of grade 3 and 4 peripheral neuropathy were higher with the concurrent versus the sequential schedule (14 versus 6%, respectively [p=0.04]).¹⁰⁰⁰⁴

In the subset analysis based on one-third of the enrolled patients who consented to EGFR testing, both the mean PFS and OS were significantly higher for the EGFR-positive than the EGFR-negative patients (PFS: 6 versus 3 months, respectively [p =0.001];¹⁰⁰⁰⁵ OS: 15 versus 7 months, respectively [p=0.046], with a corresponding HR of 0.45 and 0.58 for PFS and OS, respectively). The 1-year PFS was higher in EGFR-positive patients (20 months) compared with 3 months in EGFR-negative patients.¹⁰⁰⁰⁵

The 1-year survival and response rates were higher for the EGFR-positive than the EGFR-negative patients (1-year survival: 58 versus 32%, respectively; response rate: 45 versus 26%, respectively).¹⁰⁰⁰⁵ The disease control (all responses plus stable disease) rate was higher for the EGFR-positive patients than for the EGFR-negative patients (81% versus 55%).¹⁰⁰⁰⁵

Although the survival rates were numerically higher for EGFR-positive patients in both the concurrent and sequential groups, significance was only demonstrated for the concurrent group (HR 0.43 and 0.83 for the concurrent and sequential groups, respectively).¹⁰⁰⁰⁵

The investigators plan to perform EGFR testing using protein expression analysis by IHC; analysis of the presence and the impact of an EGFR mutation on response will be evaluated.¹⁰⁰⁰⁵

Cetuximab with Gemcitabine-Carboplatin (or Cisplatin)

BMS CA225100 is a phase 2, randomized, open-label, noncomparative study (n=131) evaluating the benefit of concurrent cetuximab in combination with a gemcitabine-platinum (carboplatin or cisplatin, selected by the investigator before randomization) containing regimen as primary treatment for stage IIIB (with a malignant pleural effusion) and stage IV NSCLC.¹⁰⁰⁰⁶ Patients were enrolled irrespective of the EGFR status.¹⁰⁰⁰⁶ All patients had an ECOG performance status of less than 2; all NSCLC histologies were included.¹⁰⁰⁰⁶

The primary end point was response rate; secondary end points were PFS, OS, disease control rate, duration of response, and time to response.¹⁰⁰⁰⁶

The objective response rate was higher with the cetuximab arm compared with chemotherapy alone (27.7 versus 18.2%, respectively).¹⁰⁰⁰⁶ The disease control (all responses plus stable disease) rate was similar for both groups (75.4 versus 74.2% for chemotherapy plus cetuximab and for chemotherapy alone, respectively).¹⁰⁰⁰⁶

Both the PFS and OS were improved with the cetuximab-containing regimen compared with chemotherapy alone (median PFS: 5.09 versus 4.21 months, respectively; OS: 11.99 versus 9.26 months, respectively).¹⁰⁰⁰⁶ The response duration is essentially similar at 5.09 and 4.9 months for the cetuximab and chemotherapy-alone arms, respectively.¹⁰⁰⁰⁶ The 1-year survival rates are higher with the cetuximab regimen (49.9%) compared with chemotherapy alone (37.5%).¹⁰⁰⁰⁶ Numerically, higher responses were reported in the cetuximab arm; however, no statistical analysis has been reported with these data.¹⁰⁰⁰⁶

The incidence of grade 3 or 4 febrile neutropenia was higher with the cetuximab arm than with the chemotherapy-only arm (4.7 versus 1.5%, respectively); grade 3 or 4 thrombocytopenia was also higher in the cetuximab than in the chemotherapy-only group (57.8 versus 44.6%, respectively).¹⁰⁰⁰⁶ Acneiform rashes were reported in 14% of patients receiving cetuximab.¹⁰⁰⁰⁶

The investigators have no plans to perform EGFR testing; additionally, no assessment for the presence of either an EGFR or KRAS mutation will be performed.¹⁰⁰⁰⁶

Discussion

Background

Epidermal growth factor receptor (EGFR) is overexpressed in 40–80% of patients with non-small cell lung cancer (NSCLC).¹⁰⁰⁰⁷ EGFR-targeted therapy using a small-molecule tyrosine kinase inhibitor (TKI) initially was evaluated in combination with chemotherapy as first-line therapy for advanced-stage NSCLC, but showed no survival benefit compared with chemotherapy alone.¹⁰⁰⁰⁸ Subsequently, cetuximab, an EGFR-monoclonal antibody, has shown activity as a single agent in relapsed and refractory patients;¹⁰⁰⁰⁹ more recently, the drug has been evaluated in combination with various chemotherapy regimens as first-line therapy for advanced-stage (i.e., stage IIIB and IV) NSCLC.^{10001 10002 10004 10006}

Results from the FLEX study, in which all patients were EGFR positive (i.e., using protein expression by IHC), demonstrated a survival advantage of 1.2 months with an 11% improvement in overall survival and a 5% improvement in 1-year survival for all patients receiving cetuximab with vinorelbine/cisplatin compared with patients receiving chemotherapy alone.¹⁰⁰⁰¹ The progression-free survival was similar for both groups.¹⁰⁰⁰¹ The survival benefit was observed across all performance-status groups, in both smokers and nonsmokers, for all histology types, in both genders, and for patients older than 65 years.¹⁰⁰⁰¹ The subgroup of patients with Asian ethnicity, in which a higher percentage of patients had prognostic characteristics commonly associated with an EGFR mutation such as adenocarcinoma histology, female gender, and a never-smoking history,¹⁰⁰¹⁰ was shown to have a 7-month improvement in survival compared with the remaining Caucasian patients.¹⁰⁰⁰¹ However, a higher percentage of Asian patients received oral TKI therapy following their initial study treatment; therefore, the contribution of additional EGFR-targeted therapy to an improved survival rate in this subgroup cannot be ruled out as a possible factor.¹⁰⁰¹¹ Although numerically higher survival rates were reported in this group, there was no statistically significant improvement in survival with the addition of cetuximab for the Asian subset.¹⁰⁰⁰¹

In the FLEX study, the overall survival (OS) for Caucasian patients (84% of the study population) was 9.6 months; the OS was 12 and 10.2 months for patients in this subgroup with adenocarcinoma (44%) and squamous (36.6%) histologies, respectively.¹⁰⁰⁰¹ The incidence of febrile neutropenia with the cetuximab and vinorelbine/cisplatin regimen was higher (22%) compared with other commonly used first-line regimens, such as carboplatin and paclitaxel administered with or without cetuximab (4–5%).^{10002 10004 10012} The activity of this regimen of cetuximab with vinorelbine and cisplatin in the presence of either an EGFR or KRAS mutation is not known at this time.¹⁰⁰¹¹ One concern is the high incidence of febrile neutropenia with this regimen, which is a clinically important consideration when selecting patients in whom treatment is noncurative and, therefore, may have a negative impact on quality of life.¹⁰⁰¹³

Conflicting data have been reported for the regimens using a combination of a platinum agent (i.e., carboplatin or cisplatin) and a taxane (i.e., paclitaxel or docetaxel) with cetuximab.^{10002 10003 10004 10005} In the BMS 099 study, in which EGFR testing was not performed, the reported PFS was similar for groups receiving cetuximab and those not receiving the drug, and, therefore, failed to meet the study objective of a 25% improvement in this end point.¹⁰⁰⁰² The median OS was slightly improved by 1.3 months with the addition of cetuximab,¹⁰⁰⁰³ although the improvement was not statistically significant; the median reported OS of 9.7 months was lower than that reported with other cetuximab-based regimens and is comparable to survival with chemotherapy alone.^{10012 10014} In the SWOG study, there was no difference in 1-year PFS and survival between the concurrent and sequential cetuximab arms; however, grade 3/4 febrile neutropenia and peripheral neuropathy rates were higher with the concurrent arm.¹⁰⁰⁰⁴ The subset analysis based on patients who had EGFR gene copy detection performed revealed an association between EGFR status and response, characterized by a statistically significant improvement in both PFS and OS in EGFR-positive patients, with a high survival of 15 months in EGFR-positive patients.¹⁰⁰⁰⁵ A subset analysis of responses for patients based on their prognostic features (e.g., ethnic background, histology, gender) has not been reported for either of the taxane-platinum based studies.^{10002 10003 10004 10005} There are plans to correlate EGFR detection in both the BMS and SWOG studies using the 2 currently available methods (IHC and FISH). ^{10002 10004} Additionally, data will be collected to determine if an association exists between the presence of an EGFR or a KRAS mutation and the impact on activity of the cetuximab-based regimen.^{10002 10004}

Gemcitabine and cisplatin (or carboplatin) with cetuximab has produced an improvement in both the median PFS, 1-year survival, and OS rates compared with chemotherapy alone in a small number of patients.¹⁰⁰⁰⁶ These responses are higher than reported with other cetuximab-containing regimens; however, in the absence of a statistical analysis, the clinical benefit cannot be fully determined.¹⁰⁰¹¹ There are no plans to establish a correlation between response and EGFR status; additionally, assessment of response in the presence of mutations will not be established with this combination.¹⁰⁰¹¹ Therefore, the use of this regimen is not fully established.¹⁰⁰⁰⁶

Summary

The predictive and prognostic value of using EGFR testing in advanced-stage NSCLC patients for the selection of cetuximab-based therapy is not fully established at this time.¹⁰⁰¹¹ Additional data are needed from ongoing studies to determine not only the clinical importance of this biomarker, but also to confirm the appropriate testing or detection method that should be used for EGFR screening.¹⁰⁰¹¹ Both EGFR (by FISH) and KRAS mutations have been shown to have predictive value as described with responses to TKI therapy in the presence of an EGFR mutation¹⁰⁰⁰⁸ and the lack of a response to cetuximab in patients with colorectal cancer who harbor a KRAS mutation.¹⁰⁰¹⁵ Information about the activity of cetuximab in the presence of either an EGFR or KRAS mutation will be useful in identifying a subset of patients for whom this therapy would be most beneficial, and thereby help in the selection of appropriate therapy using a pharmacogenomic-guided approach.¹⁰⁰¹¹

Recent data from the ECOG 4599 study have demonstrated higher survival rates with the addition of bevacizumab to the standard carboplatin-paclitaxel regimen; however, some patients are not candidates for such therapy, either based on histology (i.e., squamous-cell) or the presence of a clinically relevant medical condition, and therefore would be treated with an alternative regimen.^{10011 10014} Although data from the FLEX study have shown improved survival in EGFR-positive patients with the addition of cetuximab, the subset analysis revealed a survival of only 9.6 months for the Caucasian population.¹⁰⁰⁰² The reported survival in the BMS 099 is reported as 9.7 months.¹⁰⁰⁰³ Thus, these results are essentially no different than the overall survival of 8–10 months reported for stage IIIB/IV NSCLC patients receiving chemotherapy alone.^{10012 10013} The one exception, however, is the 5-month improvement in survival reported for EGFR-positive patients in the SWOG study.¹⁰⁰⁰⁴ PFS rates have not been significantly improved with the addition of cetuximab to current regimens, with the exception of a 2-month improvement with the gemcitabine-platinum regimen, but based only on a small number of patients.¹⁰⁰⁰⁶

Although not a full consensus recommendation by the Oncology Expert committee, vinorelbine-cisplatin with cetuximab may be considered a reasonable choice for patients who are not candidates to receive a bevacizumab-containing regimen.¹⁰⁰¹¹ The safety and efficacy of this regimen has only been established in EGFR-positive patients using EGFR protein expression testing by IHC; the selection of patients using EGFR gene copy number by FISH for this regimen is not fully validated.^{10001 10002 10004} Based on the results of the FLEX study, only patients who are confirmed as EGFR-positive should receive this combination at this time.¹⁰⁰¹¹ However, given the modest improvement in survival rates reported to date, the following important considerations must be weighed carefully in any decision to use cetuximab regimens: 1) comparative cost, 2) the resource-intensive (i.e., weekly infusions) nature of the regimen, 3) clinically important toxicity (e.g., myelosuppression and rash), and 4) compromised quality of life.^{10011 10013} Additionally, the use of this regimen should be viewed in the context of the FLEX study results, which failed to meet its study objective and therefore did not show an improvement of 20% in PFS with this regimen compared with chemotherapy alone.¹⁰⁰⁰¹

Additional data are being collected from the ongoing BMS 099 and SWOG 0342 studies.^{10002 10004} Until additional information from a subset analysis and data from the planned biomarker evaluation are collected, a population of patients for whom such therapy would provide a clinical benefit cannot be identified; therefore, the use of cetuximab with a platinum-taxane regimen as first-line therapy is not fully established at this time.¹⁰⁰¹¹ Because EGFR testing will not be performed for patients receiving the gemcitabine-platinum-cetuximab combinations in the BMS CA2251000 study, no correlations between response and biomarker expression can be made to fully establish the role of these regimens.¹⁰⁰¹¹

Cetuximab Dosage and Administration

General

• 
  

  To minimize risk of infusion-related reactions,⁴ premedication with an antihistamine (e.g., IV diphenhydramine hydrochloride 50 mg) is recommended.¹

  
  


• 
  

  In clinical studies, a test dose (i.e., 20-mg cetuximab administered IV over 10 minutes) did not reliably identify patients at risk for severe allergic reactions.^{1 4 7}

  
  

Administration

IV Administration

Administer by IV infusion.^{1 7} Do not administer by rapid IV injection, such as IV push or bolus.¹

Solution should be clear and colorless and may contain small amounts of easily visible, white, amorphous particulates.¹

Do not shake vials.¹

Use infusion pump or syringe pump to administer.¹ When using infusion pump, withdraw appropriate dose of cetuximab into sterile syringe (attached to an appropriate needle [i.e., vented needle or pin]), then transfer solution directly into sterile evacuated container (e.g., glass container) or bag (e.g., polyolefin bag [e.g., Intravia], ethylene vinyl acetate bag [e.g., Clintec], diethylhexyl phthalate [DEHP] plasticized PVC bag [e.g., Lifecare], PVC bag).¹ When using syringe pump, withdraw appropriate dose of cetuximab into sterile syringe (attached to an appropriate needle [i.e., vented needle or pin]).¹ Use a new needle for each vial of cetuximab.¹

Infusion should be piggybacked to patient's infusion line.¹ Prime administration set with cetuximab before starting infusion.¹ Administer drug through a low-protein-binding 0.22-mcm inline filter.¹

At end of infusion, flush infusion line with 0.9% sodium chloride.¹

Monitor patients for 1 hour following each infusion.^{1 7 10} May need to monitor for longer period if patient develops infusion reactions.^{1 10}

Dilution

Do not dilute solution.¹

Rate of Administration

IV loading dose: Administer over 2 hours.¹

Weekly maintenance dose: Administer over 1 hour.¹

Infusion rate should not exceed 10 mg/minute (5 mL/minute of commercially available 2-mg/mL injection).¹

Dosage

Adults

Head and Neck Cancer

Cetuximab/Radiation Combination Therapy

IV

Initially, 400 mg/m² over 2 hours as loading dose, administered 1 week prior to initiation of first course of radiation therapy.¹ Then, 250 mg/m² over 1 hour once weekly (maintenance dosage) for duration of radiation therapy (6–7 weeks); a median of 8 doses was administered in clinical studies.¹ In clinical studies, cetuximab was administered 1 hour prior to radiation therapy, beginning week 2.¹

Monotherapy

IV

Initially, 400 mg/m² over 2 hours as loading dose, followed by maintenance doses of 250 mg/m² over 1 hour once weekly until disease progression or unacceptable toxicity occurs.¹ In clinical studies, a median of 11 doses was administered.¹

Colorectal Cancer

IV

Initially, 400 mg/m² over 2 hours as loading dose, followed by maintenance doses of 250 mg/m² over 1 hour once weekly.^{1 6 7}

When used in combination with irinotecan, consult manufacturer of that drug for information on dosage, method, and sequence of administration.¹ Dosage of irinotecan used in clinical studies was 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}

In clinical studies, a median of 12 or 7 doses of cetuximab was administered in patients receiving the cetuximab-irinotecan combination regimen or cetuximab monotherapy, respectively.¹

Dosage Modification for Toxicity

Infusion-related Reactions

If mild or moderate (grade 1 or 2) infusion-related reactions occur, permanently reduce infusion rate by 50%.^{1 6}

If severe (grade 3 or 4) infusion-related reactions occur, discontinue therapy immediately and permanently.¹

Dermatologic Toxicity

Dosage modification not necessary in patients experiencing severe radiation dermatitis.¹

If severe acneiform rash occurs, temporarily delay therapy; reduce subsequent doses or discontinue therapy depending on patient's response as follows:¹

Cetuximab Dosage Modification for Severe Acneiform Rash1

Occurrence of Severe Acneiform Rash	Intervention	Outcome	Cetuximab Dosage
First occurrence	Delay infusion for 1–2 weeks	Improvement	Continue weekly maintenance dose of 250 mg/m2
		No improvement	Discontinue cetuximab
Second occurrence	Delay infusion for 1–2 weeks	Improvement	Reduce weekly maintenance dose to 200 mg/m2
		No improvement	Discontinue cetuximab
Third occurrence	Delay infusion for 1–2 weeks	Improvement	Reduce weekly maintenance dose to 150 mg/m2
		No improvement	Discontinue cetuximab
Fourth occurrence	Discontinue cetuximab

Special Populations

No special population dosage recommendations at this time.⁴

Cautions for Cetuximab

Contraindications

• 
  

  No known contraindications according to manufacturer.¹

  
  


• 
  

  Use with caution in patients with known hypersensitivity to cetuximab, murine proteins, or any ingredient in the formulation.^{1 4}

  
  

Warnings/Precautions

Warnings

Infusion-related Effects

Mild or moderate (grade 1 or 2) infusion-related effects (e.g., chills, fever, dyspnea) reported, usually occurring on first day of initial dosing.^{1 4} In clinical studies, these effects were managed by reducing infusion rate and administering antihistamines (e.g., diphenhydramine) prior to subsequent doses.¹ (See General under Dosage and Administration.)

Severe, rarely fatal infusion-related effects also reported.^{1 6} (See Boxed Warning.) If severe infusion-related effects occur, discontinue cetuximab immediately and permanently and initiate appropriate therapy (e.g., epinephrine, corticosteroids, IV antihistamines, bronchodilators, oxygen).¹

Observe patients until all infusion-related manifestations have completely resolved.¹

Cardiopulmonary Arrest

Cardiopulmonary arrest and/or sudden death reported in patients with or without CAD, arrhythmia, and/or CHF receiving cetuximab/radiation combination therapy for treatment of squamous cell carcinoma of the head and neck.¹ (See Boxed Warning.)

Pulmonary Effects

Interstitial lung disease, interstitial pneumonitis (fatal in one case), and exacerbation of preexisting fibrotic lung disease reported,^{1 4 6} usually occurring between the fourth and eleventh doses.¹

If acute onset or exacerbation of pulmonary manifestations occurs, interrupt therapy and promptly investigate.¹ If interstitial lung disease is confirmed, discontinue cetuximab and institute appropriate therapy.¹

Use in Combination with Radiation Therapy and Cisplatin

Safety of combination regimen consisting of cetuximab, radiation therapy, and cisplatin not established.¹ Serious cardiotoxicity (e.g., MI, arrhythmia, diminished cardiac output, hypotension) and death (secondary to pneumonia in one case) reported in patients receiving this combination for treatment of locally advanced squamous cell carcinoma of the head and neck.¹

Sensitivity Reactions

Dermatologic Effects

Acneiform rash (possibly severe) reported; occurred most frequently on face, upper chest, and back but could extend to extremities.¹ Generally appears within first 2 weeks and may resolve following discontinuance; however, may persist beyond 28 days.¹ If severe acneiform rash occurs, reduce subsequent dosages.¹ (See Dermatologic Toxicity under Dosage and Administration.)

Skin drying/fissuring and inflammation (e.g., blepharitis, cheilitis, cellulitis, cyst) reported.¹ May result in infectious complications; Staphylococcus aureus sepsis and abscesses requiring incision and drainage reported.¹ If adverse dermatologic effects occur, monitor patients for possible inflammatory or infectious complications and initiate appropriate therapy.¹ Consider topical and/or oral antibiotics; topical corticosteroids not recommended.¹

Major Toxicities

Electrolyte Effects

Electrolyte abnormalities (sometimes severe), including hypomagnesemia, hypocalcemia, and hypokalemia, reported.¹ May occur days to months following initiation of therapy.^{1 10}

Monitor patients periodically for hypomagnesemia, and accompanying hypocalcemia and hypokalemia, during and for ≥8 weeks following completion of therapy.^{1 10}

Provide electrolyte repletion as necessary; IV replacement therapy required in severe cases.^{1 10} Monitor for resolution of electrolyte abnormalities during and after completion of therapy.¹

Other Serious Adverse Effects

Patients receiving therapy for squamous cell carcinoma of the head and neck: Mucositis, radiation dermatitis, confusion, diarrhea.¹ Late radiation toxicity also reported.¹

Patients receiving therapy for colorectal cancer: Diarrhea, dehydration, fever, sepsis, renal failure.¹ (See Warnings and also Sensitivity Reactions under Cautions.)

Nail Disorder

Paronychial inflammation (particularly of the great toes and thumbs) reported.¹

General Precautions

EGFR Testing

Pretreatment assessment for evidence of EGFR expression is not required for patients with squamous cell carcinoma of the head and neck, since EGFR expression has been detected in nearly all patients with head and neck cancer.¹

Immunohistochemical evidence of EGFR expression was required in clinical studies of patients with colorectal cancer.¹ EGFR expression should be assessed by laboratories with demonstrated proficiency in the specific technology being utilized.¹ Improper assay performance may lead to unreliable results.¹

Immunologic Effects

Nonneutralizing anticetuximab antibodies detected at median of 44 days after initiation of therapy in some patients.¹ No known relationship between appearance of antibodies and safety and efficacy of cetuximab.¹

Specific Populations

Pregnancy

Category C.¹

Lactation

Not known whether distributed into milk.¹ Discontinue nursing during and for 60 days following last dose (due to long half-life).¹ (See Half-life under Pharmacokinetics.)

Pediatric Use

Safety and efficacy not established in pediatric patients.¹

Geriatric Use

In patients receiving therapy for head and neck cancer, median duration of locoregional control and overall survival were prolonged with the addition of cetuximab to radiation therapy in patients <65 years of age, but these findings were not confirmed in patients ≥65 years of age.¹

In patients receiving monotherapy or combination therapy for colorectal cancer, no overall differences in safety and efficacy relative to younger adults.¹

Common Adverse Effects

In combination with radiation therapy in patients with head and neck cancer: Acneiform rash, mucositis, radiation dermatitis, weight loss, xerostomia, dysphagia,