Transcript KRAS status and efficacy in the first-line treatment

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
www.OncologyEducation.ca
CRYSTAL Trial
10 Endpoint= PFS
R
N=1217
EGFR
expression
via IHC
A
N
D
O
M
I
Z
E
FOLFIRI + Cetuximab
N=608
FOLFIRI
N=609
* Cetuximab 400 mg/m2 IV week 1 then 250 mg/m2 IV weekly
1:1
Van Custem E Proc ASCO 2007
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Results
Efficacy
Grade 3/4 toxicity
FOLFIRI
N = 650 (%)
FOLFIRI +
Cetuximab
N = 648 (%)
Response Rate
39
47
Median PFS
8.0
p=0.0038
8.9
HR = 0.85 (0.73-0.99); p=0.048
1 yr PFS
23
34
Median OS
NR
NR
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Results
Patient Characteristics
ITT
n = 1198
Centrally assessed for
KRAS mutation by QTPCR exon 12/13
n =540
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
176 (51)
172 (49)
87 (45)
105 (55)
Treatment, n (%)
FOLFIRI
FOLFIRI + Cetuximab
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Results
Efficacy
Wild-type KRAS
FOLFIRI
Median PFS, mos
FOLFIRI
FOLFIRI
FOLFIRI
+ Cetux
+ Cetux
8.7
9.9
HR = 0.68; p 0.017
1yr PFS rate, %
ORR
CR
PR
SD
Mutant KRAS
25
43
8.1
7.6
HR = 1.07; p 0.75
NR
NR
43.2
0 p 0.025
43.2
59.3
1.2
58.1
40.2
36.2
0 p 0.46 0
40.2
36.2
43.8
30.8
46.0
46.7
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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
www.OncologyEducation.ca
OPUS: Phase II
R
N=338
EGFR+
Metasatic CRC
A
N
D
O
M
I
Z
E
FOLFOX + Cetuximab
N=170
FOLFOX
N=168
* Cetuximab 400 mg/m2 IV week 1 then 250 mg/m2 IV weekly
1:1
www.OncologyEducation.ca
Results
Efficacy
Response Rate
Median PFS,
months
FOLFOX+
Cetuximab
45.6%
FOLFOX
7.2
7.2
35.7%
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Results
Patient Characteristics
ITT
n = 337
Centrally assessed for
KRAS mutation by QTPCR exon 12/13
n =233
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
73 (54)
61 (46)
47 (47)
52 (53)
Treatment, n (%)
FOLFOX
FOLFOX + Cetuximab
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Results
Efficacy
Wild-type KRAS
FOLFOX
Median PFS, mos
Mutant KRAS
FOLFOX
FOLFOX
FOLFOX
+ Cetux
+ Cetux
7.2
7.7
HR = 0.57; p 0.016
8.6
5.5
HR = 1.83; p 0.019
1yr PFS rate, %
NR
NR
NR
ORR
37.0
1.4 p 0.011
35.6
60.7
3.3
57.4
48.9
32.7
4.3 p 0.11 0
44.7
32.7
16.4
4.9
36.2
CR
PR
SD
NR
51.9
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Results
Toxicity
• 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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Bottom Line for Canadian
Medical Oncologists
• 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 wildtype 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
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