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![Page 1: Individualizing Therapy for Gastrointestinal Malignancies 2010 Update Thomas J. Semrad MD, MAS Assistant Professor of Medicine UC Davis Cancer Center.](https://reader030.fdocuments.in/reader030/viewer/2022033100/56649d8a5503460f94a71381/html5/thumbnails/1.jpg)
Individualizing Therapy for Gastrointestinal Malignancies
2010 Update
Thomas J. Semrad MD, MASAssistant Professor of Medicine
UC Davis Cancer Center
![Page 2: Individualizing Therapy for Gastrointestinal Malignancies 2010 Update Thomas J. Semrad MD, MAS Assistant Professor of Medicine UC Davis Cancer Center.](https://reader030.fdocuments.in/reader030/viewer/2022033100/56649d8a5503460f94a71381/html5/thumbnails/2.jpg)
Disclosure
• Consulting or Advisory: Genomic Health, Inc
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![Page 4: Individualizing Therapy for Gastrointestinal Malignancies 2010 Update Thomas J. Semrad MD, MAS Assistant Professor of Medicine UC Davis Cancer Center.](https://reader030.fdocuments.in/reader030/viewer/2022033100/56649d8a5503460f94a71381/html5/thumbnails/4.jpg)
Individualizing Therapy in Colorectal Cancer
• Tumor– MSI– KRAS, BRAF, and others
• Host– Pharmacogenetics
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Chromosome Instability: 85% Microsatellite Instability: 15%
KRAS Mutation: 40%
BRAF Mutation:
CIMP
Colon Cancer Is More Than One Disease
10%
Watch this Space!!!
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Microsatellite Instability (MSI)• Defective DNA Mismatch
Repair (dMMR)
Nature Reviews Cancer 2004;4,769-780.
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MSI Identifies a Subset of Stage II and III Colon Cancer with a Lower Risk of Relapse
Untreated Patients
JCO 2010;28:3219-3226
MSI
MSS
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JCO 2010;28:3219-3226
Stage II Stage III
MSI
MSS
MSI Predicts for Lack of Benefit from Adjuvant 5FU
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E5202
SurgeryTumor Block Risk Assessed Based
on MSI / 18q LOH
High Risk (MSS and 18qLOH)
Low Risk(MSI or no loss
18q)
mFOLFOX6
mFOLFOX6 + bevacizumab
Observation
R
Accrual Goal 3,125
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Adjuvant 5FU: QUASAR
Lancet 2007;370:2020-2029
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RT-PCR for RNA Quantification from Fixed Paraffin-Embedded Tumor Tissue
Strand Displacementand Cleavage of Probe
Polymerization
PolymerizationCompleted
R Q
R
Q
RQ
Forward Primer
ReversePrimer
Probe
Reporter Quencher
Clark-Langone, BMC Genomics: 2007; 8:279.
Cronin et al. Am J Pathol. 2004;164:35-42.
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QUASAR: Pre-Specified Primary Endpoint: Recurrence Risk
Is there a significant relationship between the risk of recurrence and the pre-specified continuous Recurrence Score in stage II colon cancer patients randomized to surgery alone?
STROMALFAP
INHBABGN
CELL CYCLEKi-67
C-MYCMYBL2
REFERENCEATP5EGPX1PGK1UBB
VDAC2
GADD45B
RECURRENCE SCORECalculated from Tumor
Gene Expression
Kerr et al., ASCO 2009, #4000
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QUASAR Results: Colon Cancer Recurrence Score Predicts Recurrence Following Surgery
Prospectively-Defined Primary Analysis in Stage II Colon Cancer (n=711)
p=0.004Ris
k of
Re
curr
en
ce a
t 3 y
ea
rs
0%
5%
10%
15%
20%
25%
30%
35%
Recurrence Score0 10 20 30 40 50 60 70
Ris
k of
Re
curr
en
ce a
t 3 y
ea
rs
0%
5%
10%
15%
20%
25%
30%
35%
Recurrence Score0 10 20 30 40 50 60 70
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Kerr et al., ASCO 2009, #4000
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QUASAR Results: Recurrence Score, T Stage, and MMR Deficiency are Key Independent Predictors of Recurrence in
Stage II Colon Cancer
Kerr et al., ASCO 2009, #4000
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Nature Reviews Cancer 2009; 9, 489-499
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Mutated KRAS Predicts Absence of Benefit From EGFR-Targeted Antibodies
Mutated KRAS
Wild-type KRAS
N Engl J Med 2008;359:1757-65
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What We Thought We Knew: CRYSTAL
N Engl J Med 2009;360:1408-17
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Cetuximab Does Not Improve DFS in Stage III CRC
JCO 28:15s, 2010 (suppl; abstr 3508)
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MRC COINCetuximab and Oxaliplatin
• Advanced Colorectal Cancer, first line therapy• No Prior Chemotherapy for Metastatic Disease• PS 0-2• Good Organ Function• No prior EGFR IHC
• Advanced Colorectal Cancer, first line therapy• No Prior Chemotherapy for Metastatic Disease• PS 0-2• Good Organ Function• No prior EGFR IHC
5FU or capecitabineOxaliplatin
Second Line Therapy: Irinotecan based
Primary Endpoint: Overall Survival in KRAS wild-type
Secondary Endpoints:OS in KRAS mutantOS in “all wild-type”PFS, RRQOLHealth Economics
Second Line Therapy: Irinotecan based
Primary Endpoint: Overall Survival in KRAS wild-type
Secondary Endpoints:OS in KRAS mutantOS in “all wild-type”PFS, RRQOLHealth Economics
A
OxMdG: mFOLFOX6 with slightly different LVCapOx: Oxaliplatin 130mg/m2 D1; Capecitabine 1000mg/m2 D1-14 every 21 days, reduced to 850mg/m2 July 2007 due to toxicity
CapOx or OxMdG chosen before randomization; N=815 per arm
5FU or capecitabineOxaliplatinCetuximabCetuximab
5FU or capOxaliplatin
5FU or capOxaliplatin
B
C
12 Weeks
JCO 28:15s, 2010 (suppl; abstr 3502)
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JCO 28:15s, 2010 (suppl; abstr 3502)
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Biomarkers
Population N Arm A Arm B
ITT 1630 815 815
Assessed for mutation 1316 (81%) 648 668
KRAS mutated 565 (43%) 268 297
BRAF mutated 102 (8%) 57 45
NRAS mutated 50 (4%) 18 32
KRAS wild-type 729 (55%) 367 362
“All wild-type” 581 (44%) 289 292
BRAF102
KRAS565
NRAS50
Total 1316
KRAS & NRAS 11
All WT581
JCO 28:15s, 2010 (suppl; abstr 3502)
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COIN: Survival by SubgroupM
edia
n O
vera
ll S
urvi
val (
Mon
ths)
JCO 28:15s, 2010 (suppl; abstr 3502)
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COIN: Response RatesKRAS WT KRAS Mutated
Arm A Arm B Arm A Arm B
N 367 362 268 297
ORR at 12 weeks 50%50% 59%59% 41% 40%
Odds Ratio (B vs. A) OR 1.44OR 1.44P = 0.015P = 0.015
OR 0.97P = 0.877
Overall Response 57%57% 64%64% 46% 43%
Odds Ratio (B vs. A) OR 1.35OR 1.35P = 0.049P = 0.049
OR 0.88P = 0.449
JCO 28:15s, 2010 (suppl; abstr 3502)
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???Front Line Chemotherapy Plus EGFR-Targeted Antibody - KRAS Wild Type
Trial Arm RR (%) ORP-value
PFS (months)
HRP-value
OS (months)
HRP-value
MRC COINASCO 2010N = 1630
OxFdG / XELOX 5757 1.441.440.0150.015
8.6 0.9590.60
17.9 1.0370.68+ cetuximab 6464 8.6 17.0
CRYSTALASCO GI 2010
N = 1198
FOLFIRI 4040 2.072.07<0.0001<0.0001
8.48.4 0.6960.6960.00120.0012
20.020.0 0.7960.7960.00930.0093+ cetuximab 5757 9.99.9 23.523.5
OPUSJCO 2009N = 337
FOLFOX4 3737 2.5442.5440.0110.011
7.27.2 0.5700.5700.01630.0163
NRNA
+ cetuximab 6161 7.77.7 NR
PRIMEASCO GI 2010
N = 1183
FOLFOX4 48 NR0.07
8.08.0 0.800.800.020.02
19.7 0.830.07+ panitumumab 55 9.69.6 23.9
CAUTION: CROSS TRIAL COMPARISONS!!
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BRAF Mutation: Prognostic and/or Predictive?
Trial Arm RR (%) ORP-value
PFS (months)
HRP-value
OS (months)
HRP-value
CRYSTALFOLFIRI 15 NR
0.9136
5.6 0.9340.8656
10.3 0.9080.7440+ cetuximab 19 8.0 14.1
Combined CRYSTAL &
OPUS
Chemotherapy 13 1.60.4606
3.7 0.690.267
9.9 0.630.079+ cetuximab 22 7.1 14.1
Combined CRYSTAL &
OPUS
Chemotherapy 492.27
<0.001
7.70.64
<0.001
21.10.840.041+ cetuximab 61 10.9 24.8
BRAF Mutated
KRAS and BRAF Wild Type
JCO 28:15s, 2010 (suppl; abstr 3506)
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www.abcam.com
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Predictors of Benefit from Bevacizumab in Colon Cancer
?? VEGF Pathway Polymorphisms
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JCO 2005; 23: 7342-7349
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JCO 2009; 27: 5519-5528
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JCO 2010; 28: 3227-3233
N9741
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JCO 2010; 28: 3227-3233
Pharmacogenetic Hypotheses Can Be Tested in Cooperative Group Trials
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Conclusions: I• MSI
– Prognostic in Stage II and III– Predicts lack of benefit from 5FU in Stage II
• KRAS mutations– Predict lack of benefit from cetuximab
• BRAF mutation– May NOT be a good predictor for lack of benefit from
cetuximab– Suggests an awful prognosis
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Conclusions: II
• No evidence for benefit of either bevacizumab or cetuximab in adjuvant setting
• Does cetuximab combine better with irinotecan than oxaliplatin?
• Pharmacogenetic data is needed from cooperative group trials