Individualizing Therapy for Gastrointestinal Malignancies

2010 Update

Thomas J. Semrad MD, MASAssistant Professor of Medicine

UC Davis Cancer Center

Disclosure

• Consulting or Advisory: Genomic Health, Inc

Individualizing Therapy in Colorectal Cancer

• Tumor– MSI– KRAS, BRAF, and others

• Host– Pharmacogenetics

Chromosome Instability: 85% Microsatellite Instability: 15%

KRAS Mutation: 40%

BRAF Mutation:

CIMP

Colon Cancer Is More Than One Disease

10%

Watch this Space!!!

Microsatellite Instability (MSI)• Defective DNA Mismatch

Repair (dMMR)

Nature Reviews Cancer 2004;4,769-780.

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

JCO 2010;28:3219-3226

Stage II Stage III

MSI

MSS

MSI Predicts for Lack of Benefit from Adjuvant 5FU

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

Adjuvant 5FU: QUASAR

Lancet 2007;370:2020-2029

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.

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

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

| | ||| | | | | | | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| | ||| | | | | | | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||| || ||| ||||||||||| | || | |||||| |

Kerr et al., ASCO 2009, #4000

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

Nature Reviews Cancer 2009; 9, 489-499

Mutated KRAS Predicts Absence of Benefit From EGFR-Targeted Antibodies

Mutated KRAS

Wild-type KRAS

N Engl J Med 2008;359:1757-65

What We Thought We Knew: CRYSTAL

N Engl J Med 2009;360:1408-17

Cetuximab Does Not Improve DFS in Stage III CRC

JCO 28:15s, 2010 (suppl; abstr 3508)

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)

JCO 28:15s, 2010 (suppl; abstr 3502)

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)

COIN: Survival by SubgroupM

edia

n O

vera

ll S

urvi

val (

Mon

ths)

JCO 28:15s, 2010 (suppl; abstr 3502)

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)

???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!!

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)

www.abcam.com

Predictors of Benefit from Bevacizumab in Colon Cancer

?? VEGF Pathway Polymorphisms

JCO 2005; 23: 7342-7349

JCO 2009; 27: 5519-5528

JCO 2010; 28: 3227-3233

N9741

JCO 2010; 28: 3227-3233

Pharmacogenetic Hypotheses Can Be Tested in Cooperative Group Trials

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

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