www.oncologyeducation.ca kras status and efficacy in the first-line treatment of patients with...
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KRAS status and efficacy in the first-line treatment of patients with metastatic colorectal cancer (mCRC) treated with FOLFIRI with or without
cetuximab: The CRYSTAL experience
Authors: E. Van Cutsem, I. Lang, G. D'haens, V. Moiseyenko, J. Zaluski, G. Folprecht, S. Tejpar, O. Kisker, C. Stroh, P. Rougier
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CRYSTAL Trial
Van Custem E Proc ASCO 2007
RANDOMI ZE
1:11:1
FOLFIRI + CetuximabN=608
FOLFIRIN=609
10 Endpoint= PFS
N=1217EGFR
expressionvia IHC
* Cetuximab 400 mg/m* Cetuximab 400 mg/m2 2 IV week 1 then 250 mg/m IV week 1 then 250 mg/m22 IV weekly IV weekly
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ResultsEfficacy
Grade 3/4 toxicityFOLFIRI
N = 650 (%)
FOLFIRI + Cetuximab
N = 648 (%)
Response Rate 39 47
Median PFS 8.0 8.9
1 yr PFS 23 34
Median OS NR NR
HR = 0.85 (0.73-0.99); p=0.048
p=0.0038
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ResultsPatient Characteristics
n = 1198 n =540Centrally assessed for
KRAS mutation by QT-PCR exon 12/13
Wild-type KRAS(n=348)
Mutant KRAS(n=192)
Male, % 57.8 57.8
Age < 65, % 65.8 59.9
Prior adjuvant Rx, % 21.6 12.5
Treatment, n (%)FOLFIRI
FOLFIRI + Cetuximab176 (51)172 (49)
87 (45)105 (55)
ITT
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ResultsEfficacy
Wild-type KRAS Mutant KRAS
FOLFIRIFOLFIRI + Cetux
FOLFIRIFOLFIRI+ Cetux
Median PFS, mos 8.7 9.9 8.1 7.6
1yr PFS rate, % 25 43 NR NR
ORRCRPR
43.20
43.2
59.3 1.258.1
40.20
40.2
36.20
36.2
SD 43.8 30.8 46.0 46.7
HR = 0.68; p 0.017 HR = 1.07; p 0.75
p 0.025 p 0.46
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KRAS status and efficacy in the first-line treatment of patients with mCRC treated with FOLFOX with or
without cetuximab: The OPUS experience
Authors: C Bokemeyer, I Bondarenko, J Hartmann, F De Braud, C Volovat, C Stroh,J Nippgen, I Celik, P Koralewski
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OPUS: Phase II
RANDOMI ZE
1:11:1
FOLFOX + CetuximabN=170
FOLFOXN=168
N=338EGFR+
Metasatic CRC
* Cetuximab 400 mg/m* Cetuximab 400 mg/m2 2 IV week 1 then 250 mg/m IV week 1 then 250 mg/m22 IV weekly IV weekly
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ResultsEfficacy
FOLFOX+ Cetuximab
FOLFOX
Response Rate 45.6% 35.7%
Median PFS, months
7.2 7.2
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ResultsPatient Characteristics
n = 337 n =233Centrally assessed for
KRAS mutation by QT-PCR exon 12/13
Wild-type KRAS(n=134)
Mutant KRAS(n=99)
Male, % 55.2 49.5
Age < 65, % 63.4 62.6
Prior adjuvant Rx, % 18.7 17.2
Treatment, n (%)FOLFOX
FOLFOX + Cetuximab73 (54)61 (46)
47 (47)52 (53)
ITT
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ResultsEfficacy
Wild-type KRAS Mutant KRAS
FOLFOXFOLFOX + Cetux
FOLFOXFOLFOX+ Cetux
Median PFS, mos 7.2 7.7 8.6 5.5
1yr PFS rate, % NR NR NR NR
ORRCRPR
37.01.4
35.6
60.73.3
57.4
48.94.3
44.7
32.70
32.7
SD 16.4 4.9 36.2 51.9
HR = 0.57; p 0.016 HR = 1.83; p 0.019
p 0.011 p 0.11
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ResultsToxicity
• No difference in skin rash or other toxicity by KRAS status in CRYSTAL or OPUS
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STUDY COMMENTARY
• Together with Panitumumab monotherapy in 3rd line setting (Van Custem JCO 2007) these two trials demonstrate that monoclonal antibody blockade against EGFR only benefit patients with wild-type KRAS– Similar findings with EGFR TKIs in NSCLC and
pancreatic adenoCA
• No overall survival data reported for either CRYSTAL or OPUS
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• Addition of Cetuximab to first line FOLFOX or FOLFIRI only benefits patients with wild type KRAS– Biologically plausible mAb to receptor will not shut off
signaling if a downstream kinase (KRAS) is constitutively active• Addition of Cetuximab to first line FOLFOX in KRAS
mutant patients appears to be detrimental– ? Biology of this phenomenon
• Optimal sequence of biological therapy in KRAS wild-type patients remains to be determined– Should obtain KRAS mutational status on all patients where
Cetuximab is considered• NCIC CO.17 is the only trial to demonstrate OS benefit
with EGFR mAb– Retrospective survival analysis by KRAS status is eagerly
awaited
Bottom Line for Canadian Medical Oncologists