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man and wife dancing at wedding

When you see Jay's tumor shrink, his hope for a father-daughter dance grows

Confidence in choosing the right cancer treatment for your patient comes from seeing results. Experience and data have shown ERBITUX with FOLFIRI (irinotecan, fluorouracil, and leucovorin) can deliver the real, tangible results you need to see for appropriate patients with KRAS wild-type, EGFR-expressing metastatic colorectal cancer (mCRC). Because when you see results, your patient sees hope.

Metastatic Colorectal Cancer

ERBITUX is indicated for the treatment of KRAS wild-type, epidermal growth factor receptor (EGFR)-expressing, metastatic colorectal cancer (mCRC) as determined by an FDA-approved test for this use:

  • In combination with FOLFIRI (irinotecan, fluorouracil, leucovorin) for first-line treatment
  • In combination with irinotecan in patients who are refractory to irinotecan-based chemotherapy
  • As a single agent in patients who have failed oxaliplatin- and irinotecan-based chemotherapy or who are intolerant to irinotecan

Limitations of Use: ERBITUX is not indicated for treatment of RAS-mutant colorectal cancer or when the results of the RAS mutation tests are unknown.

KRAS Wild-Type, EGFR Expressing mCRC

Review efficacy results from tumor-location subgroup post hoc analyses of 3 phase III trials in RAS wild-type mCRC

See the CRYSTAL, FIRE-3, and CALGB/SWOG 80405 trials

CRYSTAL=Cetuximab combined with iRinotecan in first-line therapY for metaSTatic colorectAL cancer

CRYSTAL regimen=cetuximab with FOLFIRI

FIRE-3: FOLFIRI + cetuximab versus FOLFIRI + bevacizumab as first-line treatment for patients with mCRC

CALGB=Cancer and Leukemia Group B; SWOG=Southwest Oncology Group.

Please see CRYSTAL study design following the efficacy results below

CRYSTAL Study

CRYSTAL (NCT00154102) study and post hoc analyses: Efficacy results* in KRAS and RAS wild-type mCRC1-3

The CRYSTAL study may not be adequately powered, nor error-controlled, for subgroup analyses. Treatment differences observed in the RAS wild-type subpopulation cannot be regarded as statistically significant. The analyses described here were exploratory.

Limitations of the RAS post hoc analysis data: Only 65% of patients with KRAS wild-type tumors were evaluable for RAS status.3 RAS wild-type subpopulation data presented may not be representative of the label population.

  • The main outcome measure in the all-randomized patient population was progression-free survival (PFS) assessed by an independent review committee (IRC)1

CRYSTAL REGIMEN VS FOLFIRI ALONE

Erbitux cetuximab CRYSTAL regimen vs FOLFIRI alone

Median Overall Survival

The median overall survival data includes post hoc updated overall survival analysis based on an additional 162 events.

Data for the all-randomized patient population is CRYSTAL regimen (n equals 608) versus FOLFIRI alone (n equals 609). The median overall survival was 19.6 months for patients on the CRYSTAL regimen with a 95 percent confidence interval of 18 to 21 versus 18.5 months for patients on FOLFIRI alone, with a 95 percent confidence interval of 17 to 20. These two groups have a hazard ratio of 0.88 with a 95 percent confidence interval of 0.78 to 1.0.

Data for the KRAS wild-type subpopulation post hoc analysis is CRYSTAL regimen (n equals 320) versus FOLFIRI alone (n equals 356). The median overall survival was 23.5 months for patients on the CRYSTAL regimen with a 95 percent confidence interval of 21 to 26 versus 19.5 months for patients on FOLFIRI alone, with a 95 percent confidence interval of 17 to 21. These two groups have a hazard ratio of 0.80 with a 95 percent confidence interval of 0.67 to 0.94.

Data for the RAS wild-type subpopulation of KRAS wild-type subgroup is CRYSTAL regimen (n equals 178) versus FOLFIRI alone (n equals 189). The median overall survival was 28.4 months for patients on the CRYSTAL regimen with a 95 percent confidence interval of 24.7 to 31.6 versus 20.2 months for patients on FOLFIRI alone, with a 95 percent confidence interval of 17.0 to 24.5. These two groups have a hazard ratio of 0.69 with a 95 percent confidence interval of 0.54 to 0.88.

Objective Response Rate

The objective response equals complete response plus partial response; tumor size reduction equal to or greater than 50 percent (modified World Health Organization criteria).

The objective response rate for the all-randomized patient population was 46 percent of patients on the CRYSTAL regimen with a 95 percent confidence interval of 42 to 50 versus 38 percent of patients on FOLFIRI alone, with a 95 percent confidence interval of 34 to 42.

The objective response rate for the KRAS wild-type subpopulation post hoc analysis was 57 percent of patients on the CRYSTAL regimen with a 95 percent confidence interval of 51 to 62 versus 39 percent of patients on FOLFIRI alone, with a 95 percent confidence interval of 34 to 44.

The objective response rate for the RAS wild-type subpopulation of KRAS wild-type subgroup was 66.3 percent of patients on the CRYSTAL regimen with a 95 percent confidence interval of 58.8 to 73.2 versus 38.6 percent of patients on FOLFIRI alone, with a 95 percent confidence interval of 31.7 to 46.0.

Median Progression Free Survival

The median progression free survival was the main outcome for this data.

The median progression free survival for the all-randomized patient population was 8.9 months for the patients on the CRYSTAL regimen (n equals 608) with a 95 percent confidence interval of 8.0 to 9.4 versus 8.1 months for patients on FOLFIRI alone (n equals 609) with a 95 percent confidence interval of 7.6 to 8.8. This analysis has a hazard ratio of 0.85 with a 95 percent confidence interval of 0.74 to 0.99, with a P value equal to 0.0358, based on the stratified log-rank test.

The median progression free survival for the KRAS wild-type subpopulation post hoc analysis was 9.5 months for the patients on the CRYSTAL regimen (n equals 320) with a 95 percent confidence interval of 8.9 to 11.1 versus 8.1 months for patients on FOLFIRI alone (n equals 356) with a 95 percent confidence interval of 7.4 to 9.2. This analysis has a hazard ratio of 0.70 with a 95 percent confidence interval of 0.57 to 0.86.

The median progression free survival for the RAS wild-type subpopulation of KRAS wild-type subgroup was 11.4 months for the patients on the CRYSTAL regimen (n equals 178) with a 95 percent confidence interval of 10.0 to 14.6 versus 8.4 months for patients on FOLFIRI alone (n equals 189) with a 95 percent confidence interval of 7.4 to 9.4. This analysis has a hazard ratio of 0.56 with a 95 percent confidence interval of 0.41 to 0.76.

CI=confidence interval; HR=hazard ratio.

  • In all-randomized patients, overall survival (OS) was not significantly different at the planned, final analysis based on 838 events (HR=0.93 [95% CI: 0.8-1.1]; P=0.327)1
  • Limitations of Use: ERBITUX is not indicated for treatment of RAS-mutant colorectal cancer or when the results of the RAS mutation tests are unknown

*Post hoc updated OS analysis based on an additional 162 events.1

†Objective response=complete response + partial response; tumor size reduction ≥50% (modified World Health Organization [WHO] criteria).§2-4

‡Based on the stratified log-rank test.1

§Criteria for objective response rate (ORR)4

  • The ORR is the sum of the rate of partial response and the rate of complete response
  • Partial response: ≥50% decrease in the sum of the products of the longest diameter and the greatest perpendicular diameter of all index lesions compared to baseline, by 2 observations not less than 4 weeks apart, and no evidence of progressive disease
  • Complete response: disappearance of all measurable lesions by 2 observations no less than 4 weeks apart, without the appearance of any new lesions

CRYSTAL primary tumor location post hoc analysis: Efficacy results in patients with left- and right-sided RAS wild-type mCRC5

RAS wild-type subpopulation by primary tumor location (n=364): CRYSTAL regimen (n=175); FOLFIRI alone (n=189)

Erbitux cetuximab CRYSTAL efficacy in patients with left- and right-sided RAS wild-type mCRC

Median Overall Survival

Data for the right-sided RAS wild-type subpopulation is CRYSTAL regimen (n equals 33) versus FOLFIRI alone (n equals 51). The median overall survival of these groups was 18.5 months for patients on the CRYSTAL regimen and 15.0 months for patients on FOLFIRI alone, with a hazard ratio of 1.08 and a 95 percent confidence interval of 0.65 to 1.81.

Data for the left-sided RAS wild-type subpopulation is CRYSTAL regimen (n equals 142) versus FOLFIRI alone (n equals 138). The median overall survival of these groups was 28.7 months for patients on the CRYSTAL regimen and 21.7 months for patients on FOLFIRI alone (a difference of 7.0 months), with a hazard ratio of 0.65 and a 95 percent confidence interval of 0.50 to 0.86.

Objective Response Rate

The objective response rate for the right-sided RAS wild-type subpopulation was 42.4 percent of patients on the CRYSTAL regimen versus 33.3 percent of patients on FOLFIRI alone, with the odds ratio of 1.45 and a 95 percent confidence interval of 0.58 to 3.64.

The objective response rate for the left-sided RAS wild-type subpopulation was 72.5 percent of patients on the CRYSTAL regimen versus 40.6 percent of patients on FOLFIRI alone, with the odds ratio of 3.99 and a 95 percent confidence interval of 2.40 to 6.62.

Median Progression Free Survival

The median progression free survival for the right-sided RAS wild-type subpopulation was 8.1 months for the patients on the CRYSTAL regimen (n equals 33) versus 7.1 months for patients on FOLFIRI alone (n equals 51) with a hazard ratio of 0.87 and a 95 percent confidence interval of 0.47 to 1.62.

The median progression free survival for the left-sided RAS wild-type subpopulation was 12.0 months for the patients on the CRYSTAL regimen (n equals 142) and 8.9 months for patients on FOLFIRI alone (n equals 138) with a hazard ratio of 0.50 and a 95 percent confidence interval of 0.34 to 0.72.

OR=odds ratio.

Select Important Safety Information

Pulmonary Toxicity

ERBITUX can cause interstitial lung disease (ILD). ILD, which was fatal in one case, occurred in <0.5% of 1570 patients receiving ERBITUX in clinical trials. Monitor patients for signs and symptoms of pulmonary toxicity. Interrupt or permanently discontinue ERBITUX for acute onset or worsening of pulmonary symptoms. Permanently discontinue ERBITUX for confirmed ILD.

CRYSTAL study design and post hoc analyses1-3,5

CRYSTAL study design

CRYSTAL was a phase III, open-label, randomized, multicenter study (N=1217) conducted outside the United States that used a cetuximab product as the clinical trial material.1

  • ERBITUX provides approximately 22% higher exposure relative to the cetuximab used in this study; these pharmacokinetic data, together with the results of the CRYSTAL study and other clinical trial data, establish the efficacy of ERBITUX at the recommended dose in combination with FOLFIRI for first-line treatment of KRAS exon 2 wild-type, EGFR-expressing mCRC
  • Patients were randomized (1:1) to receive either cetuximab in combination with FOLFIRI‖ (n=608) (the CRYSTAL regimen) or FOLFIRI alone‖ (n=609) as first-line treatment until disease progression or unacceptable toxicity occurred
  • The main outcome measure of this trial was PFS assessed by an IRC. Other outcome measures were OS and ORR

KRAS post hoc analysis

  • In the KRAS wild-type subpopulation, patients received a median of 24 infusions of cetuximab (range 1 to 224)
  • KRAS mutation status was available for 89% of the patients (n=1079): 63% of patients had KRAS wild-type tumors (n=676: CRYSTAL regimen, n=320; FOLFIRI alone, n=356) and 37% of patients had KRAS-mutant tumors (n=403)

Extended RAS post hoc analysis

In this post hoc analysis of the CRYSTAL study, patient tumor samples with predefined RAS mutations other than KRAS exon 2 were evaluated. In addition, treatment effect in patients with any evaluable RAS wild-type tumor sample was also evaluated.3

  • Among patients with KRAS exon 2 wild-type tumors (n=666); 65% (n=430) were evaluable for RAS mutation status; of those, 85% (n=367) had RAS wild-type tumors
  • A post hoc analysis of efficacy data was performed on patient subgroups defined by RAS mutation status (RAS wild-type subpopulation: CRYSTAL regimen, n=178; FOLFIRI alone, n=189)

‖Patients who received cetuximab with FOLFIRI were given an initial intravenous (IV) infusion of cetuximab 400 mg/m2 followed by weekly infusions of 250 mg/m2 administered 1 hour prior to chemotherapy. For all patients, the FOLFIRI regimen included 14-day cycles of irinotecan (180 mg/m2 IV on day 1), folinic acid (400 mg/m2 [racemic] or 200 mg/m2 [L-form] IV on day 1), and fluorouracil (400 mg/m2 bolus on day 1 followed by 2400 mg/m2 as a 46-hour continuous infusion).1

Primary tumor location RAS post hoc analysis

In this post hoc analysis of the CRYSTAL study, patients with RAS wild-type mCRC were evaluated based on primary tumor location.5

  • Among patients with RAS wild-type tumors (n=367), 99% (n=364) were evaluable for primary tumor location; of those, 76% (n=280) had left-sided tumors and 23% (n=84) had right-sided tumors. Patients with transverse colon tumors were included in the right-sided analysis
  • A post hoc analysis of efficacy data was performed on patient subgroups defined by treatment arm followed by primary tumor location:
    • Left-sided tumor subpopulation: CRYSTAL regimen (with a cetuximab product), n=142; FOLFIRI alone, n=138
    • Right-sided tumor subpopulation: CRYSTAL regimen (with a cetuximab product), n=33; FOLFIRI alone, n=51

CRYSTAL study safety profile1

No new relevant safety findings were identified in the RAS subpopulation analysis3

median overall survival (OS) for erbitux with RT vs RT alone
Orange border
Incidence of selected adverse reactions occurring in ≥10% of patients with KRAS wild-type, EGFR-expressing mCRC*
Cetuximab with FOLFIRI
(n=317) 		FOLFIRI alone
(n=350)
Grades 1-4† Grades 3 and 4 Grades 1-4 Grades 3 and 4
Percentage of Patients
Hematologic
Neutropenia 49 31 42 24
Eye
Conjunctivitis 18 <1 3 0
Gastrointestinal
Diarrhea 66 16 60 10
Stomatitis 31 3 19 1
Dyspepsia 16 0 9 0
General and administration site
Pyrexia 26 1 14 1
Weight decreased 15 1 9 1
Infusion reaction‡ 14 2 <1 0
Infections
Paronychia 20 4 <1 0
Metabolism and nutrition
Anorexia 30 3 23 2
Dermatologic
Acne-like rash§ 86 18 13 <1
Rash 44 9 4 0
Dermatitis acneiform 26 5 <1 0
Dry skin 22 0 4 0
Acne 14 2 0 0
Pruritus 14 0 3 0
Palmar-plantar erythrodysesthesia syndrome 19 4 4 <1
Skin fissures 19 2 1 0
  • The CRYSTAL study used a cetuximab product. ERBITUX provides approximately 22% higher exposure compared to this product; however, the safety data provided from CRYSTAL is consistent in incidence and severity of adverse reactions with those seen for ERBITUX in this indication1

¶Adverse reactions occurring in ≥10% of patients in the cetuximab combination arm and at a higher incidence (≥5%) compared to the FOLFIRI-alone arm.

#Adverse reactions were graded using the National Cancer Institute Common Toxicity Criteria (NCI CTC), version 2.0.

**Infusion reaction defined as any event meeting the medical concepts of allergy/anaphylaxis at any time during the clinical study or any event occurring on the first day of dosing and meeting the medical concepts of dyspnea and fever or by the following events: "acute myocardial infarction," "angina pectoris," "angioedema," "autonomic seizure," "blood pressure abnormal," "blood pressure decreased," "blood pressure increased," "cardiac failure," "cardiopulmonary failure," "cardiovascular insufficiency," "clonus," "convulsion," "coronary no-reflow phenomenon," "epilepsy," "hypertension," "hypertensive crisis," "hypertensive emergency," "hypotension," "infusion related reaction," "loss of consciousness," "myocardial infarction," "myocardial ischemia," "prinzmetal angina," "shock," " sudden death," "syncope," or "systolic hypertension."

††Acne-like rash defined by the following events: "acne," "acne pustular," "butterfly rash," "dermatitis acneiform," "drug rash with eosinophilia and systemic symptoms," "dry skin," "erythema," "exfoliative rash," "folliculitis," "genital rash," "mucocutaneous rash," "pruritus," "rash," "rash erythematous," "rash follicular," "rash generalized," "rash macular," "rash maculopapular," "rash maculovesicular," "rash morbilliform," "rash papular," "rash papulosquamous," "rash pruritic," "rash pustular," "rash rubelliform," "rash scarlatiniform," "rash vesicular," "skin exfoliation," "skin hyperpigmentation," "skin plaque," "telangiectasia," or "xerosis."

FIRE-3 and CALGB/SWOG 80405 Studies

FIRE-3 study and post hoc analysis: Efficacy results in patients with mCRC6,7

FIRE-3: FOLFIRI + cetuximab versus FOLFIRI + bevacizumab as first-line treatment for patients with mCRC

The FIRE-3 study may not be adequately powered, nor error-controlled, for subgroup analyses. Treatment differences observed in the RAS wild-type subpopulation cannot be regarded as statistically significant. The analyses described here were exploratory.

FIRE-3 data should not be interpreted as suggesting that cetuximab + FOLFIRI is more effective than bevacizumab + FOLFIRI, irrespective of RAS status or primary tumor origin (left or right colon).

Limitations of the post hoc analysis data: 80% of patients in the ITT population were evaluable for RAS status (n=475) and among RAS wild-type patients (n=400), 98% were evaluable for primary tumor location (n=394). RAS wild-type subpopulation data presented may not be representative of the label population.

  • The primary endpoint in the ITT population was ORR in patients with KRAS wild-type mCRC and the result was not statistically significant6,7
Erbitux cetuximab FIRE-3 efficacy results in patients with mCRC

Median Overall Survival

Data for the all-randomized patient population (KRAS wild-type) (intent to treat population) is cetuximab plus FOLFIRI (n equals 297) versus bevacizumab plus FOLFIRI (n equals 295). The median overall survival of these groups was 28.7 months for patients on cetuximab plus FOLFIRI with a 95 percent confidence interval of 24.0 to 36.6 versus 25.0 months for patients on bevacizumab plus FOLFIRI with a 95 percent confidence interval of 22.7 to 27.6. The hazard ratio was 0.77 with a 95 percent confidence interval of 0.62 to 0.96 with a P value of 0.017.

Data for the RAS wild-type subpopulation is cetuximab plus FOLFIRI (n equals 199) versus bevacizumab plus FOLFIRI (n equals 201). The median overall survival of these groups was 33.1 months for patients on cetuximab plus FOLFIRI with a 95 percent confidence interval of 24.5 to 39.4 versus 25.0 months for patients on bevacizumab plus FOLFIRI with a 95 percent confidence interval of 23.0 to 28.1. The hazard ratio was 0.70 with a 95 percent confidence interval of 0.54 to 0.90.

The primary endpoint of Objective Response Rate equals complete response plus partial response; evaluated according to RECIST 1.0

The objective response rate for the all-randomized patient population (KRAS wild-type) (intent to treat population) was 62 percent of patients on cetuximab plus FOLFIRI with a 95 percent confidence interval of 56.2 to 67.5 versus 58 percent of patients on bevacizumab plus FOLFIRI with a 95 percent confidence interval of 52.1 to 63.7.

The objective response rate for the RAS wild-type subpopulation was 65 percent of patients on cetuximab plus FOLFIRI with a 95 percent confidence interval of 58.3 to 71.9 versus 59 percent of patients on bevacizumab plus FOLFIRI with a 95 percent confidence interval of 51.6 to 65.6.

Median Progression Free Survival

The median progression free survival for the all-randomized patient population (KRAS wild-type) (intent to treat population) was 10.0 months for the patients on cetuximab plus FOLFIRI (n equals 297) with a 95 percent confidence interval of 8.8 to 10.8 versus 10.3 months for patients on bevacizumab plus FOLFIRI (n equals 295) with a 95 percent confidence interval of 9.8 to 11.3 with a hazard ratio of 1.06 and a 95 percent confidence interval of 0.88 to 1.26 with a P value of 0.55.

The median progression free survival for the RAS wild-type subpopulation was 10.3 months for the patients on cetuximab plus FOLFIRI (n equals 199) with a 95 percent confidence interval of 9.5 to 11.8 versus 10.2 months for patients on bevacizumab plus FOLFIRI (n equals 201) with a 95 percent confidence interval of 9.3 to 11.7 with a hazard ratio of 0.97 and a 95 percent confidence interval of 0.78 to 1.20.

  • Limitations of Use: ERBITUX is not indicated for treatment of RAS-mutant colorectal cancer or when the results of the RAS mutation tests are unknown

§§Objective response=complete response + partial response; evaluated according to RECIST 1.07

FIRE-3 primary tumor location post hoc analysis: Efficacy results in patients with left- and right-sided RAS wild-type mCRC5,7

RAS wild-type subpopulation by primary tumor location (n=394): cetuximab + FOLFIRI (n=195); bevacizumab + FOLFIRI (n=199)

Erbitux cetuximab FIRE-3 efficacy in patients with left- and right-sided RAS wild-type mCRC

Median Overall Survival

Data for the right-sided RAS wild-type subpopulation is cetuximab plus FOLFIRI (n equals 38) versus bevacizumab plus FOLFIRI (n equals 50). The median overall survival of these groups was 18.3 months for patients on cetuximab plus FOLFIRI versus 23.0 months for patients on bevacizumab plus FOLFIRI with hazard ratio of 1.31 with a 95 percent confidence interval of 0.81 to 2.11.

Data for the left-sided RAS wild-type subpopulation is cetuximab plus FOLFIRI (n equals 157) versus bevacizumab plus FOLFIRI (n equals 149). The median overall survival of these groups was 38.3 months for patients on cetuximab plus FOLFIRI versus 28.0 months for patients on bevacizumab plus FOLFIRI (a difference of 10.3 months), with a hazard ratio of 0.63 and a 95 percent confidence interval of 0.48 to 0.85.

Objective Response Rate equals complete response plus partial response; evaluated according to RECIST 1.1

The objective response rate for the right-sided RAS wild-type subpopulation was 52.6 percent of patients on cetuximab plus FOLFIRI versus 50.0 percent of patients on bevacizumab plus FOLFIRI, with the odds ratio of 1.11 and a 95 percent confidence interval of 0.48 to 2.59.

The objective response rate for the left-sided RAS wild-type subpopulation was 68.8 percent of patients on cetuximab plus FOLFIRI versus 61.7 percent of patients on bevacizumab plus FOLFIRI, with the odds ratio of 1.37 and a 95 percent confidence interval of 0.85 to 2.19.

Median Progression Free Survival

The median progression free survival for the right-sided RAS wild-type subpopulation was 7.6 months for the patients on cetuximab plus FOLFIRI (n equals 38) versus 9.0 months for patients on bevacizumab plus FOLFIRI (n equals 50) with a hazard ratio of 1.44 and a 95 percent confidence interval of 0.92 to 2.26.

The median progression free survival for the left-sided RAS wild-type subpopulation was 10.7 months for the patients on cetuximab plus FOLFIRI (n equals 157) and 10.7 months for patients on bevacizumab plus FOLFIRI (n equals 149) with a hazard ratio of 0.90 and a 95 percent confidence interval of 0.71 to 1.14.

§§Objective response=complete response + partial response; evaluated according to RECIST 1.17

Select Important Safety Information

Dermatologic Toxicities

  • ERBITUX can cause dermatologic toxicities, including acneiform rash, skin drying and fissuring, paronychial inflammation, infectious sequelae (e.g., S. aureus sepsis, abscess formation, cellulitis, blepharitis, conjunctivitis, keratitis/ulcerative keratitis with decreased visual acuity, cheilitis), and hypertrichosis
    • Acneiform rash occurred in 82% of the 1373 patients who received ERBITUX across clinical trials. Severe (Grades 3 or 4) acneiform rash occurred in 10% of patients. Acneiform rash usually developed within the first 2 weeks of therapy; the rash lasted more than 28 days after stopping ERBITUX in most patients.
    • Life-threatening and fatal bullous mucocutaneous disease with blisters, erosions, and skin sloughing has been observed in patients who received ERBITUX. It could not be determined whether these mucocutaneous adverse reactions were directly related to EGFR inhibition or to idiosyncratic immune-related effects (e.g., Stevens-Johnson syndrome or toxic epidermal necrolysis).
    • Monitor patients receiving ERBITUX for dermatologic toxicities and infectious sequelae.
    • Sun exposure may exacerbate these effects. Instruct patients to limit sun exposure during ERBITUX therapy.
    • Withhold, reduce dose or permanently discontinue ERBITUX based on severity of acneiform rash or mucocutaneous disease.

FIRE-3 study design and post hoc analyses6,7

FIRE-3 study design

FIRE-3 was an open-label, randomized, multicenter, phase III trial comparing cetuximab + FOLFIRI‖‖ vs bevacizumab + FOLFIRI in first-line treatment of patients with KRAS exon 2 wild-type mCRC.6

  • Patients were randomized (1:1) to receive either FOLFIRI + cetuximab‖‖ (n=297) or FOLFIRI + bevacizumab‖‖ (n=295) as first-line treatment
  • The primary endpoint in the ITT population was objective response (complete or partial response) using RECIST 1.0, investigator-assessed. Secondary endpoints included median PFS and median OS

RAS post hoc analysis

In a post hoc analysis of the FIRE-3 study, 475 patient tumor samples were retested for other RAS mutations (exons 2-4 of both KRAS and NRAS).7

  • 400 were found to be wild-type (final RAS wild-type population) and 75 were found to have mutations to one or more of the RAS genes tested

Primary tumor location RAS post hoc analysis

In this post hoc analysis of the FIRE-3 study, patients with RAS wild-type mCRC were evaluated based on primary tumor location.5,7

  • Among patients with RAS wild-type tumors (n=400), 98% (n=394) were evaluable for primary tumor location; of those, 77% (n=306) had left-sided tumors and 22% (n=88) had right-sided tumors. Patients with transverse colon tumors were included in the right-sided analysis
  • A post hoc analysis of efficacy data was performed on patient subgroups defined by treatment arm, followed by primary tumor location:
    • Left-sided tumor subpopulation: cetuximab + FOLFIRI, n=157; bevacizumab + FOLFIRI, n=149
    • Right-sided tumor subpopulation: cetuximab + FOLFIRI, n=38; bevacizumab + FOLFIRI, n=50

‖‖On day 1 of each 14-day treatment cycle, patients treated with cetuximab + FOLFIRI received an initial IV infusion of cetuximab 400 mg/m2 over 120 minutes followed by weekly infusions of 250 mg/m2 over 60 minutes. Patients treated with bevacizumab + FOLFIRI received an initial IV infusion of bevacizumab 5 mg/kg over 90 minutes, followed 2 weeks later over 60 minutes, and over 30 minutes every 2 weeks thereafter with the first dose administered after chemotherapy and all subsequent doses administered either before or after chemotherapy. For all patients, the FOLFIRI regimen included 14-day cycles of irinotecan (180 mg/m2 IV on day 1 over 60-90 minutes), folinic acid (400 mg/m2 [racemic] on day 1 over 120 minutes), and fluorouracil (400 mg/m2 bolus on day 1 followed by 2400 mg/m2 as a 46-hour continuous infusion). Treatment was continued until disease progression, unacceptable toxicity, or a complete response was achieved.6

CALGB/SWOG 80405 study and post hoc analysis: Efficacy results in patients with KRAS wild-type mCRC8

CALGB=Cancer and Leukemia Group B; SWOG=Southwest Oncology Group.

CALGB/SWOG 80405 data should not be interpreted as suggesting that cetuximab + FOLFIRI or FOLFOX is more effective than bevacizumab + FOLFIRI or FOLFOX, irrespective of RAS status or primary tumor origin (left or right colon).

The CALGB/SWOG 80405 study may not be adequately powered, nor error-controlled, for subgroup analyses. Treatment differences observed in the RAS wild-type subpopulation cannot be regarded as statistically significant. The analyses described here were exploratory.

Limitations of the RAS post hoc analysis data: Only 59% of patients in the ITT population were evaluable for RAS status and among RAS wild-type patients (n=526), 90% were evaluable for primary tumor location (n=474). RAS wild-type subpopulation data presented may not be representative of the label population

The primary endpoint in the ITT population was OS in patients with KRAS wild-type mCRC and the result was not statistically significant.

Erbitux cetuximab CALGB/SWOG 80405 efficacy results in patients with KRAS wild-type mCRC

Median Overall Survival was the primary endpoint in this trial

Data is for the all-randomized patient population (KRAS wild-type) (intent to treat population) treated with cetuximab plus FOLFIRI/mFOLFOX6 (n equals 578) versus bevacizumab plus FOLFIRI/mFOLFOX6 (n equals 559). The median overall survival was 30.0 months for patients in the cetuximab group versus 29.0 months for patients in the bevacizumab group, with a hazard ratio of 0.88 and a 95 percent confidence interval of 0.77 to 1.01 and a P value of 0.08.

ERBITUX is only approved in combination with FOLFIRI when treating metastatic colorectal cancer. In CALGB/SWOG 80405, choice of FOLFIRI or mFOLFOX6 was at the discretion of the physician. mFOLFOX6 is defined as leucovorin, fluorouracil, and oxaliplatin.

Objective Response Rate equals complete response plus partial response and was investigator-assessed according to RECIST 1.0

The objective response rate for the all-randomized patient population (KRAS wild-type) (intent to treat population) was 59.6 percent (345 of 578) of patients on cetuximab plus FOLFIRI/mFOLFOX6 versus 55.2 percent (309 of 559) of patients on bevacizumab plus FOLFIRI/mFOLFOX6.

Median Progression Free Survival

The median progression free survival for the all-randomized patient population (KRAS wild-type) (intent to treat population) was 10.5 months for the patients on cetuximab plus FOLFIRI/mFOLFOX6 (n equals 578) versus 10.6 months with on bevacizumab plus FOLFIRI/mFOLFOX6 (n equals 559) with a hazard ratio of 0.95, a 95 percent confidence interval of 0.84 to 1.08, and a P value of 0.45.

mFOLFOX6=leucovorin, fluorouracil, and oxaliplatin

RAS wild-type subpopulation

The results for OS (HR=0.88; 95% CI: 0.72-1.08) and PFS (HR=1.03; 95% CI: 0.86-1.24) in the expanded RAS wild-type cohort were similar to those in the full cohort.

Limitations of Use: ERBITUX is not indicated for treatment of RAS-mutant colorectal cancer or when the results of the RAS mutation tests are unknown

¶¶ERBITUX is only approved in combination with FOLFIRI when treating mCRC. In CALGB/SWOG 80405, choice of FOLFIRI/mFOLFOX6 was at the discretion of the physician.

##Objective response (complete response + partial response) was investigator-assessed according to RECIST 1.0

CALGB/SWOG 80405 primary tumor location post hoc analysis: Efficacy results in patients with left- and right-sided RAS wild-type mCRC9,10

RAS wild-type subpopulation by primary tumor location (n=474); cetuximab + FOLFIRI/mFOLFOX6 (n=244); bevacizumab + FOLFIRI/mFOLFOX6 (n=230)

Erbitux cetuximab CALGB/SWOG 80405 efficacy in patients with left- and right-sided RAS wild-type mCRC

Median Overall Survival

Data is for the right-sided RAS wild-type subpopulation treated with cetuximab plus FOLFIRI/mFOLFOX6 (n equals 71) versus bevacizumab plus FOLFIRI/mFOLFOX6 (n equals 78). The median overall survival was 13.7 months for patients in the cetuximab group versus 29.2 months for patients in the bevacizumab group, with a hazard ratio of 1.36 and a 95 percent confidence interval of 0.93 to 1.99.

Data is for the left-sided RAS wild-type subpopulation treated with cetuximab plus FOLFIRI/mFOLFOX6 (n equals 173) versus bevacizumab plus FOLFIRI/mFOLFOX6 (n equals 152). The median overall survival of these groups was 39.3 months for patients in the cetuximab group and 32.6 months for patients in the bevacizumab group (a difference of 6.7 months), with a hazard ratio of 0.77 and a 95 percent confidence interval of 0.59 to 0.99.

ERBITUX is only approved in combination with FOLFIRI when treating metastatic colorectal cancer. In CALGB/SWOG 80405, choice of FOLFIRI or mFOLFOX6 was at the discretion of the physician. mFOLFOX6 is defined as leucovorin, fluorouracil, and oxaliplatin.

Objective Response Rate equals complete response plus partial response and was investigator-assessed according to RECIST 1.0

The objective response rate for the right-sided RAS wild-type subpopulation was 42.3 percent of patients on cetuximab plus FOLFIRI/mFOLFOX6 versus 39.7 percent of patients on bevacizumab plus FOLFIRI/mFOLFOX6, with an odds ratio of 1.11 and a 95 percent confidence interval of 0.61 to 2.01.

The objective response rate for the left-sided RAS wild-type subpopulation was 69.4 percent of patients on cetuximab plus FOLFIRI/mFOLFOX6 versus 57.9 percent of patients on bevacizumab plus FOLFIRI/mFOLFOX6, with an odds ratio of 1.65 and a 95 percent confidence interval of 1.16 to 2.34.

Odds ratios were adjusted for treatment arm, protocol chemotherapy, prior adjuvant therapy, prior radiotherapy, age, sex, synchronous disease, and in place primary liver metastases.

Median Progression Free Survival

The median progression free survival for the right-sided RAS wild-type subpopulation was 7.5 months for the patients on cetuximab plus FOLFIRI/mFOLFOX6 (n equals 71) versus 10.2 months for patients on bevacizumab plus FOLFIRI/mFOLFOX6 (n equals 78) with a hazard ratio of 1.64 and a 95 percent confidence interval of 1.15 to 2.36.

The median progression free survival for the left-sided RAS wild-type subpopulation was 12.7 months for the patients on cetuximab plus FOLFIRI/mFOLFOX6 (n equals 173) versus 11.2 months for the patients on bevacizumab plus FOLFIRI/mFOLFOX6 (n equals 152) with a hazard ratio of 0.84 and a 95 percent confidence interval of 0.66 to 1.06.

¶¶ERBITUX is only approved in combination with FOLFIRI when treating mCRC. In CALGB/SWOG 80405, choice of FOLFIRI/mFOLFOX6 was at the discretion of the physician.

##Objective response (complete response + partial response) was investigator-assessed according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.0.

***Adjusted for treatment arm, protocol chemotherapy, prior adjuvant therapy, prior radiotherapy, age, sex, synchronous disease, in place primary, liver metastases.10

Select Important Safety Information

Hypomagnesemia and Accompanying Electrolyte Abnormalities

  • ERBITUX can cause hypomagnesemia. Hypomagnesemia occurred in 55% of 365 patients receiving ERBITUX in study CA225-025 and two other clinical trials in patients with colorectal cancer (CRC) or head and neck cancer, including Grades 3 and 4 in 6% to 17%. In EXTREME, where a cetuximab product was administered in combination with platinum-based therapy, the addition cetuximab to cisplatin and fluorouracil resulted in an increased incidence of hypomagnesemia of any grade (14%) and of Grade 3 or 4 hypomagnesemia (7%). Hypomagnesemia of any grade occurred in 4% of patients who received cetuximab, carboplatin, and fluorouracil. No patient experienced grade 3 or 4 hypomagnesemia. The onset of hypomagnesemia and accompanying electrolyte abnormalities can occur days to months after initiating ERBITUX.
    • Monitor patients weekly during treatment for hypomagnesemia, hypocalcemia, and hypokalemia, and for at least 8 weeks following the completion of ERBITUX.
    • Replete electrolytes as necessary.

CALGB/SWOG 80405 study design and post hoc analyses8-10

CALGB/SWOG 80405 study design

CALGB/SWOG 80405 was a randomized phase III trial of cetuximab or bevacizumab with FOLFIRI or mFOLFOX6 for patients with KRAS wild-type untreated metastatic adenocarcinoma of the colon or rectum.8

  • The choice of FOLFIRI or mFOLFOX6 was made by the patient and physician before trial enrollment and randomization
  • Patients were randomized (1:1:1) to receive FOLFIRI/mFOLFOX6 + cetuximab††† (n=902), FOLFIRI/mFOLFOX6 + bevacizumab††† (n=899), or FOLFIRI/mFOLFOX6 + cetuximab + bevacizumab††† (n=533) as first-line treatment. Of these, 1137 patients with confirmed KRAS wild-type tumors received bevacizumab (n=559) or cetuximab (n=578)‡‡‡
  • The primary endpoint in the ITT population was OS in patients with KRAS wild-type mCRC. Secondary endpoints included objective response (complete or partial response) using RECIST 1.0, investigator-assessed and median PFS

Primary tumor location RAS post hoc analysis

In this post hoc analysis of the CALGB/SWOG 80405 study, primary tumor location in patients with RAS wild-type mCRC was determined from patient case report forms.9

  • Cetuximab or bevacizumab was administered with either FOLFIRI or mFOLFOX6, at the discretion of the physician
  • Among the total 474 patients with RAS wild-type mCRC, 51% (n=244) were in the cetuximab group and 49% (n=230) were in the bevacizumab group. Patients with transverse colon tumors were excluded from analysis
    • Among patients in the cetuximab group (n=244), 71% (n=173) had left-sided tumors and 29% (n=71) had right-sided tumors
    • Among patients in the bevacizumab group (n=230), 66% (n=152) had left-sided tumors and 34% (n=78) had right-sided tumors10

†††On day 1 of each 14-day treatment cycle, patients treated with cetuximab + FOLFIRI/mFOLFOX6 received an initial IV infusion of cetuximab 400 mg/m2 over 120 minutes followed by weekly infusions of 250 mg/m2 over 60 minutes. Patients treated with bevacizumab + FOLFIRI/mFOLFOX6 received an initial IV infusion of bevacizumab 5 mg/kg over 90 minutes, followed by infusions over 30-60 minutes every other week thereafter. Cetuximab or bevacizumab was administered prior to chemotherapy. The FOLFIRI regimen included 14-day cycles of irinotecan (180 mg/m2 IV on day 1 over 90 minutes), leucovorin (400 mg/m2 on day 1 over 2 hours), and fluorouracil (400 mg/m2 bolus on day 1 followed by 2400 mg/m2 as a 46-48 hour continuous infusion). The mFOLFOX6 regimen included 14-day cycles of oxaliplatin (85 mg/m2 IV on day 1 over 120 minutes), leucovorin (400 mg/m2 IV on day 1 over 2 hours), and fluorouracil (400 mg/m2 bolus on day 1 followed by 2400 mg/m2 as a 46-48 hour continuous infusion).

‡‡‡A lack of efficacy of EGFR antibodies in KRAS exon 2 mutant tumors resulted in a pivotal amendment restricting eligibility to patients with confirmed KRAS wild-type tumors within 3 years of the start of the trial. The following year, the dual antibody treatment group was closed due to failure of the dual antibody with chemotherapy combination treatment. Patient enrollment and follow-up of a revised 2-group trial (cetuximab vs bevacizumab with chemotherapy regimens) was completed after 10 years and additional amendments. The final primary analysis cohort was comprised of 1137 patients with confirmed KRAS wild-type tumors and included 804 patients randomized after and 333 patients registered before the KRAS amendment was implemented.

National Comprehensive Cancer Network® (NCCN®) recommends RAS testing at mCRC diagnosis11,12

NCCN recommends that all patients with mCRC should have tumor tissue genotyped for RAS (KRAS and NRAS) and BRAF mutations. Patients with any known KRAS mutation (exon 2, 3, 4) or NRAS mutation (exon 2, 3, 4) should not be treated with cetuximab. Microsatellite instability or mismatch repair testing is also recommended in all newly diagnosed patients with colon or rectal cancer.

Testing for KRAS, NRAS, and BRAF mutations should be performed only in laboratories that are certified under the Clinical Laboratory Improvement Amendments of 1988 (CLIA-88) as qualified to perform high complexity clinical laboratory (molecular pathology) testing.

NCCN Clinical Practice Guidelines in Oncology® (NCCN Guidelines®), Category 2A‖‖‖11,12

  • Cetuximab (ERBITUX®) is recommended first line by NCCN Guidelines® as a treatment option in combination with FOLFIRI or FOLFOX for appropriate patients with advanced or metastatic colorectal cancer (CRC); specifically patients without any known KRAS mutation (exon 2, 3, 4), NRAS mutation (exon 2, 3, 4), or BRAF mutation (eg, BRAF V600E) and for left-sided tumors only.
  • Preoperative regimens with high response rates should be considered for patients who could be converted from unresectable to resectable disease in first line

ERBITUX® (cetuximab) FDA-approved Indication1

ERBITUX is indicated for the treatment of KRAS wild-type, EGFR-expressing mCRC as determined by an FDA-approved test, in combination with FOLFIRI for first-line treatment

Limitations of Use: ERBITUX is not indicated for treatment of RAS-mutant colorectal cancer or when the results of the RAS mutation tests are unknown.

§§§Microsatellite instability (MSI) or mismatch repair (MMR) testing is also recommended in all newly diagnosed patients with colon or rectal cancer.11,12

‖‖‖Category 2A: Based upon lower-level evidence, there is uniform NCCN consensus that the intervention is appropriate.11,12

References

  1. ERBITUX (cetuximab) [package insert]. Indianapolis, IN: Eli Lilly and Company; 2021.
  2. Van Cutsem E, et al. J Clin Oncol. 2011;29(15):2011-2019.
  3. Van Cutsem E, et al. J Clin Oncol. 2015;33(7):692-700.
  4. Miller AB, et al. Cancer. 1981;47(1):207-214.
  5. Tejpar S, et al. JAMA Oncology. 2017;3:194-201.
  6. Heinemann V, et al. Lancet Oncol. 2014;15:1065-1075.
  7. Stintzing S, et al. Lancet Oncol. 2016;17:1426-1434.
  8. Venook AP, et al. JAMA. 2017;317(23):2392-2401.
  9. Venook A, et al. J Clin Oncol. 2016;34(suppl):abstract 3504.
  10. Arnold D, et al. Ann Oncol. 2017;28(8):1713-1729.
  11. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Colon Cancer V.2.2021. © National Comprehensive Cancer Network, Inc 2021. All rights reserved. Accessed January 21, 2021. To view the most recent and complete version of the guidelines, go online to NCCN.org. NCCN makes no warranties of any kind whatsoever regarding their content, use, or application and disclaims any responsibility for their application or use in any way.
  12. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Rectal Cancer V.1.2021. © National Comprehensive Cancer Network, Inc 2020. All rights reserved. Accessed December 22, 2020. To view the most recent and complete version of the guidelines, go online to NCCN.org. NCCN makes no warranties of any kind whatsoever regarding their content, use, or application and disclaims any responsibility for their application or use in any way.

IMPORTANT SAFETY INFORMATION

Warning:

WARNING: INFUSION REACTIONS AND CARDIOPULMONARY ARREST

Infusion Reactions - ERBITUX can cause serious and fatal infusion reactions. Severe (Grades 3 and 4) infusion reactions occurred in 2.2% of patients receiving ERBITUX in clinical trials.

  • The risk of anaphylactic reactions may be increased in patients with a history of tick bites, red meat allergy, or in the presence of IgE antibodies directed against galactose-α-1,3-galactose (alpha-gal). Consider testing patients for alpha-gal IgE antibodies using FDA-cleared methods prior to initiating ERBITUX. Negative results for alpha-gal antibodies do not rule out the risk of severe infusion reactions.
  • Approximately 90% of the severe infusion reactions occurred with the first infusion of ERBITUX despite premedication with antihistamines.
    • Serious infusion reactions, requiring immediate medical intervention, included symptoms of rapid onset of airway obstruction (bronchospasm, stridor, hoarseness), hypotension, shock, loss of consciousness, myocardial infarction, and/or cardiac arrest. Immediately interrupt and permanently discontinue ERBITUX infusion for serious infusion reactions.
    • Caution must be exercised with every ERBITUX infusion as infusion reactions may occur during or several hours following completion of the infusion.
    • Premedicate with a histamine-1 (H1) receptor antagonist as recommended.
    • Monitor patients for at least 1 hour following each ERBITUX infusion in a setting with resuscitation equipment and other agents necessary to treat anaphylaxis. In patients requiring treatment for infusion reactions, monitor for more than 1 hour to confirm resolution of the reaction. Interrupt the infusion and upon recovery, resume the infusion at a slower rate or permanently discontinue ERBITUX based on severity.
Cardiopulmonary Arrest - ERBITUX can cause cardiopulmonary arrest. Cardiopulmonary arrest or sudden death occurred in 2% of 208 patients with squamous cell carcinoma of the head and neck receiving radiation therapy and ERBITUX in BONNER. In 3 patients with prior history of coronary artery disease, death occurred 27, 32, and 43 days respectively after the last dose of ERBITUX. One patient with no prior history of coronary artery disease died one day after the last dose of ERBITUX. In EXTREME, fatal cardiac disorders and/or sudden death occurred in 3% of the 219 patients with squamous cell carcinoma of the head and neck treated with a cetuximab product in combination with platinum-based therapy and fluorouracil.
  • Carefully consider the use of ERBITUX with radiation therapy, or with platinum-based therapy with fluorouracil, in head and neck cancer patients with a history of coronary artery disease, congestive heart failure, or arrhythmias.
  • Closely monitor serum electrolytes, including serum magnesium, potassium, and calcium, during and after ERBITUX therapy.

Pulmonary Toxicity

  • ERBITUX can cause interstitial lung disease (ILD). ILD, which was fatal in one case, occurred in <0.5% of 1570 patients receiving ERBITUX in clinical trials. Monitor patients for signs and symptoms of pulmonary toxicity. Interrupt or permanently discontinue ERBITUX for acute onset or worsening of pulmonary symptoms. Permanently discontinue ERBITUX for confirmed ILD.

Dermatologic Toxicities

  • ERBITUX can cause dermatologic toxicities, including acneiform rash, skin drying and fissuring, paronychial inflammation, infectious sequelae (e.g., S. aureus sepsis, abscess formation, cellulitis, blepharitis, conjunctivitis, keratitis/ulcerative keratitis with decreased visual acuity, cheilitis), and hypertrichosis
    • Acneiform rash occurred in 82% of the 1373 patients who received ERBITUX across clinical trials. Severe (Grades 3 or 4) acneiform rash occurred in 10% of patients. Acneiform rash usually developed within the first 2 weeks of therapy; the rash lasted more than 28 days after stopping ERBITUX in most patients.
    • Life-threatening and fatal bullous mucocutaneous disease with blisters, erosions, and skin sloughing has been observed in patients who received ERBITUX. It could not be determined whether these mucocutaneous adverse reactions were directly related to EGFR inhibition or to idiosyncratic immune-related effects (e.g., Stevens-Johnson syndrome or toxic epidermal necrolysis).
    • Monitor patients receiving ERBITUX for dermatologic toxicities and infectious sequelae.
    • Sun exposure may exacerbate these effects. Instruct patients to limit sun exposure during ERBITUX therapy.
    • Withhold, reduce dose or permanently discontinue ERBITUX based on severity of acneiform rash or mucocutaneous disease.

Risks Associated with Use in Combination with Radiation and Cisplatin

  • ERBITUX is not indicated for the treatment of SCCHN in combination with radiation and cisplatin.
  • In a controlled study, 940 patients with locally advanced SCCHN were randomized 1:1 to receive either ERBITUX in combination with radiation therapy and cisplatin, or radiation therapy and cisplatin alone. The addition of ERBITUX resulted in an increase in the incidence of Grade 3 and 4 mucositis, radiation recall syndrome, acneiform rash, cardiac events, and electrolyte disturbances compared to radiation and cisplatin alone.
  • Adverse reactions with fatal outcome were reported in 4% of patients in the ERBITUX combination arm and 3% in the control arm.
  • In the ERBITUX arm, 2% experienced myocardial ischemia compared to 0.9% in the control arm.
  • The addition of ERBITUX to radiation and cisplatin did not improve progression-free survival (the primary endpoint).

Hypomagnesemia and Accompanying Electrolyte Abnormalities

  • ERBITUX can cause hypomagnesemia. Hypomagnesemia occurred in 55% of 365 patients receiving ERBITUX in study CA225-025 and two other clinical trials in patients with colorectal cancer (CRC) or head and neck cancer, including Grades 3 and 4 in 6% to 17%. In EXTREME, where a cetuximab product was administered in combination with platinum-based therapy, the addition cetuximab to cisplatin and fluorouracil resulted in an increased incidence of hypomagnesemia of any grade (14%) and of Grade 3 or 4 hypomagnesemia (7%). Hypomagnesemia of any grade occurred in 4% of patients who received cetuximab, carboplatin, and fluorouracil. No patient experienced grade 3 or 4 hypomagnesemia. The onset of hypomagnesemia and accompanying electrolyte abnormalities can occur days to months after initiating ERBITUX.
    • Monitor patients weekly during treatment for hypomagnesemia, hypocalcemia, and hypokalemia, and for at least 8 weeks following the completion of ERBITUX.
    • Replete electrolytes as necessary.

Increased Tumor Progression, Increased Mortality, or Lack of Benefit in Patients with Ras-Mutant mCRC

  • ERBITUX is not indicated for the treatment of patients with CRC that harbor somatic mutations in exon 2 (codons 12 and 13), exon 3 (codons 59 and 61), and exon 4 (codons 117 and 146) of either K-Ras or N-Ras and hereafter referred to as "Ras" or when the Ras status is unknown.
  • Retrospective subset analyses of Ras-mutant and wild-type populations across several randomized clinical trials, including CRYSTAL, were conducted to investigate the role of Ras mutations on the clinical effects of anti-EGFR-directed monoclonal antibodies. Use of cetuximab in patients with Ras mutations resulted in no clinical benefit with treatment related toxicity. Confirm Ras mutation status in tumor specimens prior to initiating ERBITUX.

Embryo-Fetal Toxicity

  • Based on animal data and its mechanism of action, ERBITUX can cause fetal harm when administered to a pregnant woman. There are no available data for ERBITUX exposure in pregnant women. In an animal reproduction study, intravenous administration of cetuximab once weekly to pregnant cynomolgus monkeys during the period of organogenesis resulted in an increased incidence of embryolethality and abortion. Disruption or depletion of EGFR in animal models results in impairment of embryo-fetal development including effects on placental, lung, cardiac, skin, and neural development. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with ERBITUX and for 2 months after the last dose of ERBITUX. Verify pregnancy status in females of reproductive potential prior to initiating ERBITUX.

Adverse Reactions

  • The most common adverse reactions (all grades; incidence ≥25%) seen in patients with carcinomas of the head and neck receiving ERBITUX in combination with radiation therapy (n=208) versus radiation alone (n=212) (BONNER) were acneiform rash (87% vs 10%), radiation dermatitis (86% vs 90%), weight loss (84% vs 72%), asthenia (56% vs 49%), nausea (49% vs 37%), increased alanine transaminase (43% vs 21%), increased aspartate transaminase (38% vs 24%), increased alkaline phosphatase (33% vs 24%), fever (29% vs 13%), emesis (29% vs 23%), pharyngitis (26% vs 19%) and dehydration (25% vs 19%). The most common grade 3 and 4 adverse reactions for ERBITUX in combination with radiation therapy (≥10%) versus radiation alone included: radiation dermatitis (23% vs 18%), acneiform rash (17% vs 1%), and weight loss (11% vs 7%). The overall incidence of late radiation toxicities (any grade) was higher for patients receiving ERBITUX in combination with radiation therapy, versus radiation therapy alone. The following sites were affected: salivary glands (65% vs 56%), larynx (52% vs 36%), subcutaneous tissue (49% vs 45%), mucous membrane (48% vs 39%), esophagus (44% vs 35%), skin (42% vs 33%). The incidence of Grade 3 or 4 late radiation toxicities was similar between radiation therapy alone and the ERBITUX with radiation treatment groups.
  • The most common adverse reactions (all grades; incidence ≥25%) seen in patients with carcinomas of the head and neck receiving a cetuximab product in combination with platinum-based therapy and fluorouracil (CT) (n=219) versus CT alone (n=215) (EXTREME) were acneiform rash (70% vs 2%), nausea (54% vs 47%), infection (44% vs 27%), rash (28% vs 2%), diarrhea (26% vs 16%) and anorexia (25% vs 14%). The most common grade 3 and 4 adverse reaction for a cetuximab product in combination with CT (≥10%) versus CT alone was infection (11% vs 8%). Because ERBITUX provides approximately 22% higher exposure relative to the cetuximab product used in EXTREME, the data provided above may underestimate the incidence and severity of adverse reactions anticipated with ERBITUX for this indication. However, the tolerability of the recommended dose is supported by safety data from additional studies of ERBITUX.
  • The most common adverse reactions (all grades; incidence ≥25%) seen in patients with K-Ras wild-type, EGFR-expressing mCRC treated with a cetuximab product in combination with FOLFIRI (n=317) versus FOLFIRI alone (n=350) (CRYSTAL) were acne-like rash (86% vs 13%), diarrhea (66% vs 60%), neutropenia (49% vs 42%), rash (44% vs 4%), stomatitis (31% vs 19%), anorexia (30% vs 23%), dermatitis acneiform (26% vs <1%) and pyrexia (26% vs 14%). The most common grade 3 and 4 adverse reactions (≥10%) included: neutropenia (31% vs 24%), acne-like rash (18% vs <1%), and diarrhea (16% vs 10%). ERBITUX provides approximately 22% higher exposure compared to the cetuximab product used in CRYSTAL; however, the safety data from CRYSTAL is consistent in incidence and severity of adverse reactions with those seen for ERBITUX in this indication.
  • The most common adverse reactions (all grades; incidence ≥25%) seen in patients with K-Ras wild-type, EGFR-expressing mCRC treated with ERBITUX + best supportive care (BSC) (n=118) versus BSC alone (n=124) (CA225-025) were rash/desquamation (95% vs 21%), fatigue (91% vs 79%), nausea (64% vs 50%), pain-other (59% vs 37%), dry skin (57% vs 15%), constipation (53% vs 38%), dyspnea (49% vs 44%), pruritus (47% vs 11%), neuropathy-sensory (45% vs 38%), diarrhea (42% vs 23%), vomiting (40% vs 26%), headache (38% vs 11%), infection without neutropenia (38% vs 19%), other-dermatology (35% vs 7%), stomatitis (32% vs 10%), nail changes (31% vs 4%), cough (30% vs 19%), insomnia (27% vs 13%) and fever (25% vs 16%). The most common grade 3 and 4 adverse reactions (≥10%) included: fatigue (31% vs 29%), pain-other (18% vs 10%), rash/desquamation (16% vs 1%), dyspnea (16% vs 13%), other-gastrointestinal (12% vs 5%), and infection without neutropenia (11% vs 5%).
  • The most common adverse reactions (all grades) seen in patients with EGFR-expressing recurrent mCRC (n=354) treated with ERBITUX plus irinotecan in clinical trials (CP02-9923 and BOND) were acneiform rash (88%), asthenia/malaise (73%), diarrhea (72%), and nausea (55%). The most common grade 3-4 adverse reactions included: diarrhea (22%), leukopenia (17%), asthenia/malaise (16%), and acneiform rash (14%).
  • The most common adverse reactions (all grades; incidence ≥25%) seen in patients with BRAF V600E mutation-positive mCRC treated with ERBITUX in combination with encorafenib (N=216) versus ERBITUX with irinotecan or ERBITUX with FOLFIRI (N=193) (BEACON) were fatigue (51% vs 50%), nausea (34% vs 41%), diarrhea (33% vs 48%), dermatitis acneiform (32% vs 43%), abdominal pain (30% vs 32%), decreased appetite (27% vs 27%), arthralgia (27% vs 3%) and rash (26% vs 26%). Other clinically important adverse reactions occurring in <10% of patients who received ERBITUX in combination with encorafenib were pancreatitis. The most common laboratory abnormalities (all grades; incidence ≥20%) seen in patients receiving ERBITUX in combination with encorafenib versus ERBITUX with irinotecan or ERBITUX with FOLFIRI (BEACON) were anemia (34% vs 48%) and lymphopenia (24% vs 35%).

Use in Specific Populations

  • Lactation: There is no information regarding the presence of ERBITUX in human milk, the effects on the breastfed infant, or the effects on milk production. Human IgG antibodies can be excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from ERBITUX, advise women not to breastfeed during treatment with ERBITUX and for at least 2 months after the last dose of ERBITUX.
  • Pediatric Use: The safety and effectiveness of ERBITUX in pediatric patients have not been established. No new safety signals were identified in pediatric patients when ERBITUX in combination with irinotecan was administered in an open-label, single-arm dose-finding study in 27 patients with refractory solid tumors aged 1 to 12 years old and in 19 patients aged 13 to 18 years old.
  • Geriatric Use: In SCCHN clinical studies of ERBITUX there were insufficient number of patients >65 years of age to determine whether they respond differently from younger patients.

CE HCP ISI_ALL 14SEP2022

INDICATION

Metastatic Colorectal Cancer
ERBITUX is indicated for the treatment of KRAS wild-type, epidermal growth factor receptor (EGFR)-expressing, metastatic colorectal cancer (mCRC) as determined by an FDA-approved test for this use:

  • In combination with FOLFIRI (irinotecan, fluorouracil, leucovorin) for first-line treatment
  • In combination with irinotecan in patients who are refractory to irinotecan-based chemotherapy
  • As a single agent in patients who have failed oxaliplatin- and irinotecan-based chemotherapy or who are intolerant to irinotecan

Limitations of Use: ERBITUX is not indicated for treatment of RAS-mutant colorectal cancer or when the results of the RAS mutation tests are unknown

ERBITUX is indicated, in combination with encorafenib, for the treatment of adult patients with mCRC with a BRAF V600E mutation, as detected by an FDA-approved test, after prior therapy

Head and Neck Cancer

  • ERBITUX, in combination with radiation therapy (RT), is indicated for the initial treatment of locally or regionally advanced squamous cell carcinoma of the head and neck (SCCHN)
  • ERBITUX is indicated in combination with platinum-based therapy and fluorouracil (CT) for the first-line treatment of patients with recurrent locoregional disease or metastatic SCCHN
  • ERBITUX, as a single agent, is indicated for the treatment of patients with recurrent or metastatic SCCHN for whom prior platinum-based therapy has failed
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