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
- 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
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)
Select Important Safety Information
- 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 + FOLFIRIǁǁ 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 + cetuximabǁǁ (n=297) or FOLFIRI + bevacizumabǁǁ (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
ǁǁOn 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