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 FOLFIRIǁ (n=608) (the CRYSTAL regimen) or FOLFIRI aloneǁ (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)

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

ǁPatients 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

Indications and Safety Summary WARNING: INFUSION REACTIONS AND CARDIOPULMONARY ARREST
WARNING: INFUSION REACTIONS AND CARDIOPULMONARY ARREST
Indications

Head and Neck Cancer

ERBITUX® (cetuximab) is approved:

  • ERBITUX® (cetuximab), 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

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.

IMPORTANT SAFETY INFORMATION FOR ERBITUX® (cetuximab)

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).
  • 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 9.7% 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 in ERBITUX clinical trials (incidence ≥25%) include cutaneous adverse reactions (including rash, pruritus, and nail changes), headache, diarrhea, and infection.
  • 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 reactions 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%), pruritis (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%).
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 mCRC clinical studies, no overall differences in safety or efficacy of ERBITUX were observed between patients >65 years of age and younger patients. 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.

Please see full Prescribing Information for ERBITUX, including Boxed Warnings regarding infusion reactions and cardiopulmonary arrest.

CE HCP ISI_ALL 03JUL2018

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