Transcript Document 7418624

ECCO 2009 GI Update:
Focus on EGFR Inhibitors in
Metastatic Colorectal CA
(mCRC)
Scott Berry
Sunnybrook Odette Cancer Centree
www.OncologyEducation.ca
Overview
• EGFR Inhibitors in mCRC
– NEW DATA:
– Pmab in combination with chemo data
» 1st Line with FOLFOX
» 2nd Line with FOLFIRI
– Cetuximab in combination with
CAPOX/FOLFOX - MRC COIN Trial
– Updated cetuximab 1st line data
• CRYSTAL - updated
• OPUS – updated
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What did we know
before ECCO 2009?
www.OncologyEducation.ca
Statistically
Significant
Results
In Red
FIRST
LINE
KRAS
WT
CRYSTAL
(FOLFIRI+/Cetux)
RR %
Median
PFS/TTP
(mos)
59 vs 43
9.9 vs 8.7
mos
(HR=0.68)
SECOND
LINE
EPIC
(Iri +/- cetux)
P-mab
(Pmab vs BSC)
61 vs 37
7.7 vs 7.2
Mos
(HR=0.57)
?
NR
3.98 vs 2.79
Mos
(HR=0.77)
P=0.095
NR
17 vs 0
12.3 vs 7.3
Weeks
(HR=0.45)
NR
(Crossover)
NR
3.8 vs 1.9
Mos
(HR=0.40)
9.5 vs 4.8
Mos
(HR=0.55)
THIRD
LINE
NCIC CO.17
(Cetux vs BSC)
24.9 vs 21.0
(HR0.84)
P=0.22
(10 Outcome)
OPUS
(Rand Phase II
FOLFOX +/- Cetux)
Median OS
(mos)
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What did we find at
ECCO2009?
FIRST LINE
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“PRIME” Study Design
N= 656 KRAS WT
(1183 total 92% evaluated for KRAS)
1o Outcome: PFS
FOLFOX4
+ Pmab 6 mg/kg q 2 wks
R
FOLFOX4
mCRC
No prior oxali
> 6 mos after adj
5FU
ECOG 0-2
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RESULTS
FOLFOX
FOLFOX
+Pmab
p-value
Response
Rate
48%
55%
p=0.07
PFS
(median)
8 mos
9.6 mos
p=0.02
NE
HR=0.83
p=0.16
OS
(median)
18.8
Gr 3/4 TOXICITY
FOLFOX (%)
FOLFOX
+Pmab (%)
Patients with any event
73
80
Skin toxicity
1
30
Neutropenia
47
37
Diarrhea
10
20
Stomatitis
3
6
Hypomagnesemia
<1
6
Paronychia
0
2
Pulmonary embolismb
4
3 (2 deaths)
Infusion-related reaction
(panitumumab)
-
<1
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CRYSTAL Trial Updated
10 Endpoint= PFS
R
N=1217
EGFR
expression
via IHC
A
N
D
O
MI
ZE
FOLFIRI + Cetuximab
N=608
FOLFIRI
N=609
* Cetuximab 400 mg/m2 IV week 1 then 250 mg/m2 IV weekly
1:1
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OPUS: Rand Phase II
Updated
R
A
N
N=338
D
EGFR+
Metasatic CRC O
MI
ZE
FOLFOX + Cetuximab
N=170
FOLFOX
N=168
* Cetuximab 400 mg/m2 IV week 1 then 250 mg/m2 IV weekly
1:1
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%
Evaluated
for KRAS
%
KRAS WT
CRYSTAL
88%
63%
OPUS
93%
57%
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UPDATED CRYSTAL RESULTS
FOLFIRI
FOLFIRI
+Cetuximab
p-value
Response
Rate (%)
40%
57%
p<0.0001
PFS
(median)
8.4 mos
9.9 mos
p=0.0012
OS
(median)
20 mos
23.5 mos
p=0.01
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UPDATED OPUS RESULTS
FOLFOX
FOLFOX
+Cetuximab
p-value
Response
Rate
34%
57%
p=0.003
PFS
(median)
7.2 mos
8.3 mos
p=0.006
OS
(median)
18.5 mos
22.8 mos
p=0.38
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MRC COIN Study Design
N= 729 KRAS WT
(80 % analyzed,
56% WT)
1o Outcome: OS
R
CAPOX/ FOLFOX
66% RECEIVED CAPOX
CAPOX/ FOLFOX + CETUXIMAB
First Line
mCRC
PS0-2
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RESULTS
CAPOX/
FOLFOX
CAPOX/
FOLFOX
+ CETUX
NS
PFS (median)
OS
(median)
p-value
17.9 mos
17.0 mos
p=0.68
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TOXICITY
CAPOX/FOLFOX
(%)
CAPOX/FOLFOX
+ Cetux
(%)
Diarrhea
14
25
Rash
<1
21
Lethargy
19
26
HFS
4
11
Hypomagnesemia
0
5
Peripheral Neuropathy
19
14
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STUDY COMMENTARY
• Capecitabine Arm - Analyses not
complete but:
– Had much higher rates of non-haem toxicity
leading to dose reductions and trial
amendment - reduction of dose form 2000
mg/m2 to 1700 mg/m2 (Adams, Br J Cancer, 2009)
– Hope to have updated analysis at ASCO GI
2010 further examining the issue of efficacy
and toxicity of capecitabine cetuximab
combination and impact on overall trial
results
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STUDY COMMENTARY
• Median survivals in both study arms
lower than other contemporary first
line chemo /biologic trials
– ? patient population
• 9% > 75
• 8% ECOG 2
– ? access to subsequent line tx options
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What did we find out at
ECCO 2009?
SECOND LINE
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Study Design
N= 597 KRAS WT
(1186 total 92% evaluated for KRAS)
1o Outcome:
PFS and OS
FOLFIRI
+ Pmab 6 mg/kg q 2 wks
R
FOLFIRI
mCRC
Progression < 6 mos
after 1 prior Therapy
No prior Iri
ECOG 0-2
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RESULTS
FOLFIRI
FOLFIRI
+Pmab
p-value
Response
Rate (%)
10%
35%
p<0.001
PFS
(median)
3.9 mos
5.9 mos
p=0.004
OS
(median)
12.5 mos
14.5 mos
p=0.12
www.OncologyEducation.ca
Gr 3/4 TOXICITY
FOLFIRI
FOLFIRI
+Pmab
Patients with any event
52
73
Skin toxicity
2
37
Diarrhea
9
14
Stomatitis
3
8
Pulmonary embolism3
2
5
Dehydration
2
3
Hypomagnesemia
<1
3
Paronychia
<1
3
Infusion-related reaction
(panitumumab)
-
<1
Fatal adverse events
6
4
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Summing Up:
What do we know
after ECCO 2009?
First Line Trials:
KRAS WT
(Significant Results in Red)
CRYSTAL
(FOLFIRI+/-Cetux)
RR %
Median
PFS/TTP
(mos)
59 vs 43
9.9 vs 8.7
(HR=0.68)
Van Cutsem, NEJM
PRIME
(FOLFOX+/-Pmab)
55 vs 48
(10 Outcome)
23.5 vs 20
(HR=0.80)
9.6 vs 8.0
(HR=0.80)
NS
(10 Outcome)
COIN
(CapeOx/FOLFOX+/-Cetux)
OPUS
(Rand Phase II
FOLFOX +/- Cetux)
Median OS
(mos)
57 vs 34
NS
17.0 vs 17.9
(HR=1.04)
P=0.68
8.3 vs 7.2
(HR=0.57)
22.8 vs 18.5
(HR=0.86)
p=0.38
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Second Line Trials:
KRAS WT
RR %
Median
PFS/TTP
(mos)
Median OS
(mos)
NR
4.0 vs 2.8
(HR=0.77)
P=0.095
NR
35 vs 10
5.9 vs 3.9
(HR=0.73)
14.5 vs 12.5
(HR=0.85)
P=0.11
(Significant Results in Red)
EPIC
(Iri +/- cetux)
FOLFIRI +/Pmab
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Bottom Line for Canadian Medical
Oncologists (1)
– EGFR Inhibitors in mCRC - Survival
benefit now demonstrated:
• in 3rd line as monotherapy
• with FOLFIRI + Cetux 1st line
• FOLFIRI + Cetux emerges as credible 1st line
option for KRAS WT patients
» ...but not a funded option in Canada at this time
– NCIC CRC.5 will address issue of which chemo +
biolologic combination is superior first line
» Chemo + Bevacizumab vs Chemo + Cetuximab
» Double biologic arm dropped by intergroup
www.OncologyEducation.ca
CALGB 80405 / CRC5
NCIC Chair: S Berry
FOLFOX or FOLFIRI, and
bevacizumab
Previously
untreated
patients
with mCRC
R
FOLFOX or FOLFIRI, and
cetuximab
X
FOLFOX or FOLFIRI,
bevacizumab and cetuximab
Primary Endpoint:
Overall Survival
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Bottom Line for Canadian Medical
Oncologists (2)
• EGFR Inhibitors in mCRC - PFS benefit seen
with
– FOLFOX + Pmab first line
– FOLFIRI + Pmab second line
– Further analyses of Pmab combos awaited
• MRC COIN Trial
– ? choice of chemo NB : preliminary signal re CAPOX +
cetuximab - further information/analyses of efficacy and
safety of COIN trial needed - hopefully available at
ASCO GI 2010
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