ecco 2009 gi update: focus on egfr inhibitors in metastatic colorectal ca (mcrc)
DESCRIPTION
ECCO 2009 GI Update: Focus on EGFR Inhibitors in Metastatic Colorectal CA (mCRC). Scott Berry Sunnybrook Odette Cancer Centree. Overview. EGFR Inhibitors in mCRC NEW DATA: Pmab in combination with chemo data 1st Line with FOLFOX 2nd Line with FOLFIRI - PowerPoint PPT PresentationTRANSCRIPT
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ECCO 2009 GI Update:Focus on EGFR Inhibitors in
Metastatic Colorectal CA (mCRC)
Scott Berry
Sunnybrook Odette Cancer Centree
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?
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StatisticallySignificant
ResultsIn Red
KRASWT
RR %Median
PFS/TTP(mos)
Median OS(mos)
FIRSTLINE
CRYSTAL(FOLFIRI+/-
Cetux)59 vs 43
9.9 vs 8.7 mos
(HR=0.68)(10 Outcome)
24.9 vs 21.0(HR0.84)P=0.22
OPUS(Rand Phase II
FOLFOX +/- Cetux)61 vs 37
7.7 vs 7.2Mos
(HR=0.57)?
SECONDLINE
EPIC(Iri +/- cetux)
NR
3.98 vs 2.79Mos
(HR=0.77)P=0.095
NR
THIRD LINE
P-mab(Pmab vs BSC)
17 vs 012.3 vs 7.3
Weeks(HR=0.45)
NR(Crossover)
NCIC CO.17(Cetux vs BSC)
NR3.8 vs 1.9
Mos(HR=0.40)
9.5 vs 4.8 Mos
(HR=0.55)
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What did we find at ECCO2009? FIRST LINE
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R
FOLFOX4 + Pmab 6 mg/kg q 2 wks
FOLFOX4
N= 656 KRAS WT(1183 total - 92% evaluated for KRAS)
1o Outcome: PFS
“PRIME” Study Design
mCRCNo prior oxali> 6 mos after adj 5FUECOG 0-2 www.OncologyEducation.ca
RESULTS
FOLFOXFOLFOX+Pmab
p-value
Response Rate 48% 55% p=0.07
PFS(median) 8 mos 9.6 mos p=0.02
OS (median) 18.8 NE
HR=0.83p=0.16
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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 embolismb4 3 (2 deaths)
Infusion-related reaction (panitumumab) - <1
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CRYSTAL Trial Updated
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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OPUS: Rand Phase IIUpdated
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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%Evaluated for KRAS
%KRAS WT
CRYSTAL 88% 63%
OPUS 93% 57%
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UPDATED CRYSTAL RESULTS
FOLFIRIFOLFIRI
+Cetuximabp-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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FOLFOXFOLFOX
+Cetuximabp-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
UPDATED OPUS RESULTS
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R
CAPOX/ FOLFOX
CAPOX/ FOLFOX + CETUXIMAB
N= 729 KRAS WT(80 % analyzed,56% WT)
1o Outcome: OS
MRC COIN Study Design
First Line mCRC
PS0-2
66% RECEIVED CAPOX
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RESULTS
CAPOX/FOLFOX
CAPOX/ FOLFOX+ CETUX
p-value
PFS (median) NS
OS (median) 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
What did we find out at ECCO 2009? SECOND LINE
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R
FOLFIRI + Pmab 6 mg/kg q 2 wks
FOLFIRI
N= 597 KRAS WT(1186 total - 92% evaluated for KRAS)
1o Outcome: PFS and OS
Study Design
mCRCProgression < 6 mos after 1 prior TherapyNo prior IriECOG 0-2
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RESULTS
FOLFIRIFOLFIRI+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
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Gr 3/4 TOXICITYFOLFIRI 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
Summing Up:What do we know after ECCO 2009?
First Line Trials:KRAS WT
(Significant Results in Red)RR %
Median PFS/TTP
(mos)
Median OS(mos)
CRYSTAL(FOLFIRI+/-Cetux)
Van Cutsem, NEJM
59 vs 439.9 vs 8.7(HR=0.68)
(10 Outcome)
23.5 vs 20(HR=0.80)
PRIME(FOLFOX+/-Pmab)
55 vs 489.6 vs 8.0(HR=0.80)
(10 Outcome)
NS
COIN(CapeOx/FOLFOX+/-Cetux)
NS17.0 vs 17.9(HR=1.04)
P=0.68
OPUS(Rand Phase II
FOLFOX +/- Cetux)57 vs 34
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
(Significant Results in Red)RR %
Median PFS/TTP
(mos)
Median OS(mos)
EPIC(Iri +/- cetux)
NR4.0 vs 2.8(HR=0.77)P=0.095
NR
FOLFIRI +/- Pmab
35 vs 105.9 vs 3.9(HR=0.73)
14.5 vs 12.5(HR=0.85)
P=0.11
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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
FOLFOX or FOLFIRI, and bevacizumab
FOLFOX or FOLFIRI, and cetuximab
Previously untreated patients with mCRC
FOLFOX or FOLFIRI, bevacizumab and cetuximab
R
Primary Endpoint: Overall Survival
CALGB 80405 / CRC5NCIC Chair: S Berry
X www.OncologyEducation.ca
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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