Extended median overall survival (OS) in the KRAS wild-type subpopulation1
CRYSTAL regimen vs FOLFIRI alone
Post hoc analysis: OS in the KRAS wild-type subpopulation (n=676)
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Reset- 2-year survival rates of patients: 45% for the CRYSTAL regimen vs 37% for FOLFIRI alone*
- 3-year survival rates of patients: 26% for the CRYSTAL regimen vs 18% for FOLFIRI alone†
*2-year survival rate for CET + CT: (144/320) x 100% = 45%; for CT: (132/356) x 100% = 37%.
†3-year survival rate for CET + CT: (82/320) x 100% = 26%; for CT: (64/356) x 100% = 18%.
CRYSTAL RAS wild-type post hoc analysis: Median OS in mCRC3
CRYSTAL regimen vs FOLFIRI alone
Median OS in the RAS wild-type subpopulation of the KRAS wild-type subgroup (n=367)
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ResetLimitations of the post hoc analysis data: Only 65% of patients with KRAS wild-type tumors were evaluable for RAS status. RAS wild-type subpopulation data presented may not be representative of the label population.
The CRYSTAL study was not adequately powered, nor error-controlled, for subgroup analyses. Treatment differences observed in these subgroups cannot be regarded as statistically significant. The analyses described here were exploratory.
CET=EU-approved cetuximab; CT=FOLFIRI.
View study design View safety profile View NCCN recommendationNearly 6 out of 10 patients in the KRAS wild-type subpopulation had at least a 50% reduction in tumor size1
CRYSTAL regimen vs FOLFIRI alone
Post hoc analysis: Objective response rate (ORR)* in the KRAS wild-type subpopulation (n=676)
In the CRYSTAL study and post hoc analysis, ORRs were evaluated utilizing modified WHO criteria.†2-4
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ResetCRYSTAL RAS wild-type post hoc analysis: Tumor response rate* in mCRC3
CRYSTAL regimen vs FOLFIRI alone
ORR* in the RAS wild-type subpopulation of the KRAS wild-type subgroup (n=367)
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ResetLimitations of the post hoc analysis data: Only 65% of patients with KRAS wild-type tumors were evaluable for RAS status. RAS wild-type subpopulation data presented may not be representative of the label population.
The CRYSTAL study was not adequately powered, nor error-controlled, for subgroup analyses. Treatment differences observed in these subgroups cannot be regarded as statistically significant. The analyses described here were exploratory.
*Objective response=complete response + partial response; tumor size reduction ≥50% (modified WHO criteria).2-4
†Criteria for ORRs4
- 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 study design and post hoc analyses1-3
CRYSTAL was a phase III, open-label, randomized, multicenter study (N=1217) conducted outside the US that used European Union (EU)-approved cetuximab as the clinical trial material for EGFR-expressing metastatic colorectal cancer (mCRC).
KRAS subpopulation in the CRYSTAL study
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Reset- ERBITUX provides approximately 22% higher exposure relative to the EU-approved cetuximab; these pharmacokinetic data, together with the results of this trial and other clinical trial data, establish the efficacy of ERBITUX at the recommended dose in combination with FOLFIRI for first-line treatment of KRAS wild-type mCRC
- Patients were randomized (1:1) to receive either EU-approved cetuximab in combination with FOLFIRI* (n=608) (CRYSTAL regimen) or FOLFIRI alone* (n=609) as first-line treatment until disease progression or unacceptable toxicity occurred
- The main outcome measure was progression-free survival in all randomized patients; secondary endpoints were overall survival and response rate. Progression-free survival was derived from an assessment by an independent review committee (IRC)
- In the KRAS wild-type subpopulation (n=676), patients received a median of 26 infusions of EU-approved cetuximab (range 1-224)
- Post hoc analyses of efficacy data were performed on patient subgroups defined by KRAS mutation status
CRYSTAL study: Extended RAS post hoc analysis
In another 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
RAS subpopulation of the KRAS wild-type subgroup
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Reset- 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
*Patients treated with EU-approved cetuximab + FOLFIRI received an initial IV infusion of EU-approved cetuximab 400 mg/m2 and 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 5-fluorouracil (400 mg/m2 bolus on day 1 followed by 2400 mg/m2 as a 46-hour continuous infusion).1
†676 patients with KRAS wild-type tumors were enrolled. Of those, 666 received study treatment.
IV=intravenous.
CRYSTAL study safety profile1
No new relevant safety findings were identified in the RAS subpopulation analysis3
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Reset- The CRYSTAL study used EU-approved cetuximab. US-licensed ERBITUX® (cetuximab) provides approximately 22% higher exposure to cetuximab relative to the EU-approved cetuximab. The data provided for the CRYSTAL study are consistent in incidence and severity of adverse reactions with those seen for ERBITUX in this indication. The tolerability of the recommended dose is supported by the safety data from additional studies of ERBITUX
*Adverse reactions occurring in at least 10% of ERBITUX combination arm with a frequency of at least 5% greater than that seen in the FOLFIRI arm.
†Adverse reactions were graded using the NCI CTC, V 2.0.
‡Infusion-related reaction is 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 using MedDRA preferred terms: “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 ischaemia,” “prinzmetal angina,” “shock,” “sudden death,” “syncope,” or “systolic hypertension.”
MedDRA=Medical Dictionary for Regulatory Activities; NCI CTC=National Cancer Institute Common Toxicity Criteria.
Estimated distribution of RAS mutations* in mCRC5
- KRAS and NRAS are closely related members of the RAS oncogene family6
- Previously, 58% of patients were thought to have KRAS wild-type exon 2
- It is now known there are other RAS mutations that had not been identified
- An estimated 53% of mCRC tumors harbor RAS mutations*
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Reset*RAS mutations are defined as somatic mutations in exon 2 (codons 12 and 13), exon 3 (codons 59 and 61), and exon 4 (codons 117 and 146) of either KRAS or NRAS.
†Other RAS mutations defined as KRAS exon 2 wild-type mCRC that harbors mutations in KRAS exon 3 or 4 or NRAS exons 2-4.
National Comprehensive Cancer Network® (NCCN®) recommends RAS testing at mCRC diagnosis7,8
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ResetERBITUX (cetuximab) FDA-approved Indication1
ERBITUX is indicated for the treatment of KRAS wild-type, epidermal growth factor receptor (EGFR)-expressing metastatic colorectal cancer (mCRC) as determined by FDA-approved tests for this use in combination with FOLFIRI (irinotecan, 5-fluorouracil, leucovorin) for first-line treatment.
Limitation of Use: ERBITUX is not indicated for treatment of RAS-mutant colorectal cancer or when the results of the RAS mutation tests are unknown.
*NCCN recommends that all patients with metastatic colorectal cancer should have tumor tissue genotyped for RAS (KRAS exon 2 or non-exon 2 and NRAS) and BRAF mutations. Microsatellite instability (MSI) or mismatch repair (MMR) testing should also be performed for all patients with metastatic disease.
REFERENCES
- ERBITUX (cetuximab) [package insert]. Indianapolis, IN: Eli Lilly and Company, its subsidiaries or affiliates.
- Van Cutsem E, et al. J Clin Oncol. 2011;29(15):2011-2019.
- Van Cutsem E, et al. J Clin Oncol. 2015;33(7):692-700.
- Miller AB, et al. Cancer. 1981;47(1):207-214.
- Sorich MJ, et al. Ann Oncol. 2015;26(1):13-21.
- Custodio A, Feliu J. Crit Rev Oncol Hematol. 2013;85(1):45-81.
- Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Colon Cancer V.2.2017. © National Comprehensive Cancer Network, Inc 2017. All rights reserved. Accessed April 10, 2017. 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.
- Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Rectal Cancer V.3.2017. © National Comprehensive Cancer Network, Inc 2017. All rights reserved. Accessed April 10, 2017. 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.