asco 2009 highlights in gastrointestinal malignancies axel grothey professor of oncology mayo clinic...

ASCO 2009Highlights in Gastrointestinal

Malignancies

ASCO 2009Highlights in Gastrointestinal

Malignancies

Axel Grothey

Professor of Oncology

Mayo Clinic Rochester

Axel Grothey

Professor of Oncology

Mayo Clinic Rochester

Adjuvant Therapy of Colon CancerAdjuvant Therapy of Colon Cancer

• LBA 04 NSABP C-08 Wolmark

• 4000 Oncotype QUASAR Kerr

• 4001 PETACC-3 Tejpar

• 4002 PETACC-3 Roth

• 4010 Elderly pts McCleary

• LBA 04 NSABP C-08 Wolmark

• 4000 Oncotype QUASAR Kerr

• 4001 PETACC-3 Tejpar

• 4002 PETACC-3 Roth

• 4010 Elderly pts McCleary

History of adjuvant therapy of colon cancer

• 5-FU/lev superior to surgery alone

• 5-FU/LV superior to surgery alone

• 5-FU/LV superior to 5-FU/lev

• 6- and 12-month treatment cycles equivalent

• Lev unnecessary

• High-dose and low-dose LV equivalent

• Monthly and weekly treatment equivalent

• LV5FU2 and monthly bolus equivalent

1990 1994 1998 2002

Moertel et al. Ann Intern Med. 1995;122:321.Francini et al. Gastroenterol. 1994;106:899.Wolmark et al. Proc Am Soc Clin Oncol. 1996;15:205. AbstractO’Connell et al. J Clin Oncol. 1998;16:295.Haller et al. Proc Am Soc Clin Oncol. 1998;17:256a. Abstract 982.Andre et al. Proc Am Soc Clin Oncol. 2002. Abstract 529.

Beyond 5-FU in the adjuvant settingBeyond 5-FU in the adjuvant setting

Completed studies:

• Oxaliplatin (MOSAIC, NSABP C-07)

• Irinotecan (CALGB 89803, ACCORD-2, PETACC-3)

• Capecitabine (X-ACT)

• Bevacizumab (NSABP C-08)

Ongoing studies:

• CAPOX (XELOXA)

• Bevacizumab (AVANT, E5202)

• Cetuximab in KRAS wt CC (N0147, PETACC-8)

Completed studies:

• Oxaliplatin (MOSAIC, NSABP C-07)

• Irinotecan (CALGB 89803, ACCORD-2, PETACC-3)

• Capecitabine (X-ACT)

• Bevacizumab (NSABP C-08)

Ongoing studies:

• CAPOX (XELOXA)

• Bevacizumab (AVANT, E5202)

• Cetuximab in KRAS wt CC (N0147, PETACC-8)

MOSAIC: Study DesignMOSAIC: Study Design

Primary end-point: disease-free survival

Secondary end-points: safety, overall survival

Primary end-point: disease-free survival

Secondary end-points: safety, overall survival

n=2246

Enrollment:Oct 1998–Jan 2001 (146 centres; 20 countries)

• Completely resected colon cancer

• Stage II, 40%; Stage III, 60%

• Age 18–75 years

• KPS ≥60

• No prior chemotherapy

R

LV5FU2

FOLFOX4(LV5FU2 + oxaliplatin 85 mg/m²)

(n=1123)

(n=1123)

LV5FU2, Leucovorin 200 mg/m2 iv over 2 hours followed by 5-fluorouracil 400 mg/m2 bolus and 5-fluorouracil 600 mg/m2 iv over 22 hours on Days 1 and 2, every 14 days; FOLFOX4, LV5FU2 + oxaliplatin 85 mg/m2 iv over 2 hours on Day 1

MOSAIC: Disease-free Survival - Final Update

MOSAIC: Disease-free Survival - Final Update

5-year DFS %

HR [95% CI] p-value FOLFOX4 LV5FU2

ITT 73.3 67.4 0.80

[0.68–0.93]

0.003

Stage III 66.4 58.9 0.78

[0.65–0.93]

0.005

Stage II 83.7 79.9 0.84

[0.62–1.14]

0.258

High-risk stage II n=576

82.1 74.9 0.74

[0.52–1.06]

—

Low-risk stage II n=323

86.3 89.1 1.22

[0.66–2.26]

—

Data cut-off: June 2006

Δ7.5

Δ7.2

“High-risk” Stage II Colon Cancer“High-risk” Stage II Colon Cancer

• Clinico-pathological parameters (MOSAIC)• T4 tumors• Obstruction/perforation• Lymphatic or vascular invasion• Undifferentiated histology• Less than 10 (12) Ln examined

• Molecular parameters• LOH 18q• MSS• Other?

• Clinico-pathological parameters (MOSAIC)• T4 tumors• Obstruction/perforation• Lymphatic or vascular invasion• Undifferentiated histology• Less than 10 (12) Ln examined

• Molecular parameters• LOH 18q• MSS• Other?

MOSAIC: OS: Stage II and Stage IIIMOSAIC: OS: Stage II and Stage III

Data cut-off: January 2007

FOLFOX4 stage II

LV5FU2 stage II

FOLFOX4 stage III

LV5FU2 stage III

Overall survival (months)

Pro

bab

ilit

y

1.0

0.8

0.6

0.4

0.2

0

0.9

0.7

0.5

0.3

0.1

0 6 12 18 24 6030 36 42 48 54 66 9672 78 84 90

HR [95% CI]

Stage II 1.00 [0.71–1.42]

Stage III 0.80 [0.66–0.98]

0.1%

4.4%

p=0.996

p=0.029

Andre JCO 2009

Long-term SafetyLong-term Safety

Data cut-off: January 2007

Peripheral Sensory Neuropathy

Evaluable patients n=811

Grade 0 84.3%

Grade 1 12.0%

Grade 2 2.8%

Grade 3 0.7%

0

10

20

30

40

50

60

DuringTx

6months

1-year 2-year 3-year 4-year

Grade 1

Grade 2

Grade 3

Andre JCO 2009

Treatment of Colorectal Cancer in Elderly Patients: ACCENT Database


• Median age of diagnosis of CRC in the United States is 71 years

• Previous analyses have shown that elderly patients (≥70 years) with CRC benefit from treatment with IV fluoropyrimidines in both the adjuvant and metastatic settings

• This analysis reviewed the efficacy of newer therapies in older patients

• Patient population was derived the ACCENT database • 10,499 pts <70 years, 2,170 pts ≥70 years• 6 phase III trials compared IV FU to combinations with

irinotecan, oxaliplatin, or oral FU (capecitabine and UFT/LV) in stage II/III colon cancer

• Endpoints were overall survival (OS), disease free survival (DFS), and time to recurrence (TTR)

• Median age of diagnosis of CRC in the United States is 71 years

• Previous analyses have shown that elderly patients (≥70 years) with CRC benefit from treatment with IV fluoropyrimidines in both the adjuvant and metastatic settings

• This analysis reviewed the efficacy of newer therapies in older patients

• Patient population was derived the ACCENT database • 10,499 pts <70 years, 2,170 pts ≥70 years• 6 phase III trials compared IV FU to combinations with

irinotecan, oxaliplatin, or oral FU (capecitabine and UFT/LV) in stage II/III colon cancer

• Endpoints were overall survival (OS), disease free survival (DFS), and time to recurrence (TTR)

Folprecht. J Clin Oncol. 2008;26:1443-1451.McCleary. ASCO 2009. Abstract 4010.

Elderly Patients: Efficacy of FOLFOX Pooled Analysis C-07/MOSAIC

Elderly Patients: Efficacy of FOLFOX Pooled Analysis C-07/MOSAIC

* Values < 1 favor experimental arm

Age

Endpoint*HR (95% CI)

Experimental vs Control IV 5-FU/LV Deaths within 6 mos

Exp vs Ctrl % (p-value)

DFS OS TTP

<70n = 3,977

0.77(0.68,0.86)

0.81(0.71,0.93)

0.76(0.67,0.86)

0.81 v 0.81 (p=1.0)

≥ 70n = 703

1.04(0.80,1.35)

1.19(0.90,1.57)

0.92(0.69,1.23)

2.57 v 1.37 (p=0.25)

Interactionof age bytreatment p-value

0.016 0.037 0.21

McCleary, ASCO 2009, Abstract 4010



• Limitations of study• ACCENT does not track:

• Toxicity• Dose intensity • Co-morbidity

• These data do not contradict earlier studies showing the benefit of adjuvant therapy with 5-FU/LV vs. surgery alone in elderly patients

• Limitations of study• ACCENT does not track:

• Toxicity• Dose intensity • Co-morbidity

• These data do not contradict earlier studies showing the benefit of adjuvant therapy with 5-FU/LV vs. surgery alone in elderly patients

McCleary. ASCO 2009. Abstract 4010.

Forest Plots of Hazard Ratios – DFSForest Plots of Hazard Ratios – DFS

0.2 0.4 0.6 0.8 1 1.2 1.4 1.6 1.8 2 2.2

Hazard Ratio

Age < 70

Age >= 70

Oxaliplatin

Oral

Irinotecan

Overall

McCleary, N. ASCO 2009

2009 Update of MOSAIC Trial2009 Update of MOSAIC Trial

Andre JCO 2009

No benefit in DFS withFOLFOX vs 5-FU/LV forpatients > 65 yrs !

X-ACT: Cape vs Mayo - 5-year DFS

(median follow-up 6.8 years)

X-ACT: Cape vs Mayo - 5-year DFS

(median follow-up 6.8 years)5-year n DFS (%)

Capecitabine 1, 004 60.8

5-FU/LV 983 56.7

1.0

0.8

0.6

0.4

0.2

00 6 42 48 78 96

Months

HR=0.88 (95% CI: 0.77–1.01)NI margin 1.20

12 18 24 30 36 54 60 66 72 84 90

ITT population

Est

imat

ed p

rob

abil

ity

ITT (intent-to-treat) population; NI = non-inferiorityTwelves C, et al. Eur J Cancer Suppl

2007;5:1 (Abstract 1LB)

102

Test of non-inferiority p<0.0001Test of superiority p=0.0682

Chemo/radiotherapy-naïve

stage III colon cancer

Bolus 5-FU/LVMayo Clinic or Roswell Park

CAPOXCapecitabine 1,000mg/m2 b.i.d. days 1–15

Oxaliplatin 130mg/m2 day 1 q3w

Schmoll HJ, et al. J Clin Oncol 2007;25:4217–23

XELOXA: phase III trial of CAPOX in the adjuvant setting

XELOXA: phase III trial of CAPOX in the adjuvant setting

• Primary endpoint: disease-free survival• Primary endpoint: disease-free survival

n=944

n=942

RANDO MISATION

duration of therapy: 24 weeks

Trial open 4/03 – 10/04 Final data at ESMO 2009

Adjuvant Trials in Colon Cancer with Cetuximab (KRAS wild-type!)

Adjuvant Trials in Colon Cancer with Cetuximab (KRAS wild-type!)

Stage III colon cancer (N=2400)

PETACC 8FOLFOX4 6m

FOLFOX4 6m +Cetuximab 6m

Stage III colon cancer (N=3600)

Intergroup N0147

mFOLFOX6 6m

mFOLFOX6 6m +Cetuximab 6m

Adjuvant Trials in Colon Cancer with Bevacizumab

Adjuvant Trials in Colon Cancer with Bevacizumab

Stage II/III colon cancer (N=3450)

XELOX 6m +Bevacizumab 12m

FOLFOX4 6m +Bevacizumab 12m

AVANT FOLFOX4 6m

Stage II/III colon cancer (N=2710)

25% Stage II

mFOLFOX6 6m

mFOLFOX6 6m +Bevacizumab 12m

NSABP C-08

Reported at ASCO2009

NSABP C-08NSABP C-08

RR

mFOLFOX6 q2wk X 6 mo

BEV* q2wk X 1 yr

*5mg/kgN=2710 pts25% stage II Wolmark et al ASCO 2009

NSABP C-08Accrual

NSABP C-08Accrual

mFF6 mFF6+B

Randomized

Lost / Ineval

Analysis

1356

18

1338

1354

16

1334

Wolmark et al ASCO 2009

mFF6 mFF6+B

< 60 yr 58.3 58.2Male 49.8 49.9Stage II (0) 24.9 24.9Stage III (1-3) 45.4 45.5Stage III (4+) 29.7 29.6

NSABP C-08Patient Characteristics


<0.001

<0.001

<0.0001

<0.0001

P

1.70.3Wound Comp

2.70.8Proteinuria

11.16.3Pain

121.8Hypertension

mFF6+BmFF6

Allegra et al JCO May 4, 2009

Median Duration of Bev = 11.5 months

NSABP C-08 Grade 3+ Toxicities Increased with Bevacizumab (%)

NSABP C-08 – DFSNSABP C-08 – DFS

0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5

020

4060

8010

0

Ev 3yDFSmFF6+B 291 77.4mFF6 312 75.5

HR 0.89P 0.15


0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5

6070

8090

100 NSABP C-08 – DFSNSABP C-08 – DFS

Ev 3yDFSmFF6+B 291 77.4mFF6 312 75.5

HR 0.89P 0.15


NSABP C-08 HR over Time

0.0004

0.0040.02

0.05 0.08


NSABP C-08

1.0 1.5 2.0 2.5 3.0 3.5

Ev

mFF6+B 216mFF6 190

HR 1.07P 0.48

Event-free at 1 Yr

0.0 0.5 1.0

6070

8090

100

DFS at 1 Yr

Ev 1yDFS mFF6+B 75 94.3mFF6 122 90.7

HR 0.60P 0.0004

∆ 3.6

Time-Treatment Interaction P = 0.001


0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5

6070

8090

100 NSABP C-08 – DFSNSABP C-08 – DFS

Ev 3yDFSmFF6+B 291 77.4mFF6 312 75.5

HR 0.89P 0.15

Scans?


0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5

020

4060

80100

Ev 3yDFSmFF6+B 40 87.4

mFF6 47 84.7

HR 0.82P 0.35

DFS Stage II

Δ 2.7

0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5

020

4060

80100

Ev 3yDFS

mFF6+B 251 74.2mFF6 265 72.4

HR 0.90P 0.25

DFS Stage III

Δ 1.8

NSABP C-08


mFF6mFF6 mFF6+BmFF6+B PP

Recurrence (N)Recurrence (N) 248248 227227 NSNS

Death (N)Death (N) 146146 132132 NSNS

Second Ca (N)Second Ca (N) 4646 4747 NSNS

2yS Post Rec (%)2yS Post Rec (%) 4141 3737 NSNS

Rec Mult Sites (%)Rec Mult Sites (%) 1818 1818 NSNS

Sites of RecSites of Rec –– –– NSNS

NSABP C-08 Status at 36 mo Med Follow-up


Stage II and Stage III Colon Cancers Are Different Diseases!

Stage II and Stage III Colon Cancers Are Different Diseases!

ACCENT Database:Time from Recurrence to Death by Stage

Log Rank P-Value = <0.0001

0

20

40

60

80

100

0 1 2 3 4 5 6 7 8Time (Years)

% A

live

Stage II (N=1153)

Stage III (N=4550)

Total (N=5703)

O’Connell, et al. JCO 2008

Molecular Marker (%) Stage II (n = 420)

Stage III (n = 984) P Value

p53 overexpression 30 37 .01

SMAD4 loss 9 13 .02

Thymidylate synthase 43 29 .0001

Telomerase 40 48 .06

MSI-H 22 12 .0001

18q LoH 63 70 .04

KRAS 36 37 .67

BRAF 8 8 .90

PETACC 3: Stage-Specific Molecular Markers

PETACC 3: Stage-Specific Molecular Markers

• PETACC 3: 5-FU/LV + irinotecan vs 5-FU/LV in stage II/III CC• Translational study in 1404 pts with suitable biopsy material

• PETACC 3: 5-FU/LV + irinotecan vs 5-FU/LV in stage II/III CC• Translational study in 1404 pts with suitable biopsy material

Roth AD, et al. GI Cancers Symposium 2009. Abstract 288; ASCO 2009.

Defective MMR - Colon cancerDefective MMR - Colon cancer

• Characterized by presence of MSI & loss of MLH1, MSH2, MSH6 or PMS2 expression

• ~15% of Sporadic CC, >90% loss of MLH1

• Clinical Correlations: Right sided, Female, Early stage, Better prognosis

• Tumors: Poorly differentiated, Signet-ring-cell, Lymphocytic infiltration, near diploid

• dMMR cells resistant to 5-FU1,2

• Characterized by presence of MSI & loss of MLH1, MSH2, MSH6 or PMS2 expression

• ~15% of Sporadic CC, >90% loss of MLH1

• Clinical Correlations: Right sided, Female, Early stage, Better prognosis

• Tumors: Poorly differentiated, Signet-ring-cell, Lymphocytic infiltration, near diploid

• dMMR cells resistant to 5-FU1,2

1Carethers, 1999; 2Arnold 2003

Defective MMR vs MSIDefective MMR vs MSI

• Microsatellites (MS) = small DNA segments that consist of repetitive nucleotides of generally 100-200 base pairs

• prone to replication errors which can change their length

• DNA mismatch repair (MMR) proteins consist of hMLH1, hMSH2, hMSH6, hPMS2, hMSH3, and hMLH3

• MMR proteins can be deficient due to• mutations of genes (e.g. HNPCC/Lynch) – 5% of CRC• methylation of promoter region – 15-20% of sporadic CRC

• Test method for dMMR phenptype:• Analysis of MS lengths using 5 specific DNA markers

• MSI-H: MSI in at least 2 of 5 markers, MSI-L: MSI in only 1 marker, MSS: no instability detected

• IHC for MMR proteins: MLH1, MSH2 most important (>90%)

• Microsatellites (MS) = small DNA segments that consist of repetitive nucleotides of generally 100-200 base pairs

• prone to replication errors which can change their length

• DNA mismatch repair (MMR) proteins consist of hMLH1, hMSH2, hMSH6, hPMS2, hMSH3, and hMLH3

• MMR proteins can be deficient due to• mutations of genes (e.g. HNPCC/Lynch) – 5% of CRC• methylation of promoter region – 15-20% of sporadic CRC

• Test method for dMMR phenptype:• Analysis of MS lengths using 5 specific DNA markers

• MSI-H: MSI in at least 2 of 5 markers, MSI-L: MSI in only 1 marker, MSS: no instability detected

• IHC for MMR proteins: MLH1, MSH2 most important (>90%)

Pooled data (N=1027)Pooled data (N=1027)

Trial Treatment N % Stage II % dMMR

784852 5FU/LEV 117 30% 14%

INT 0035 5FU/LEV 215 50% 18%

874651 5FU/LV 66 19% 12%

GIVIO 5FU/LV 183 52% 16%

FFCD 5FU/LV 154 66% 19%

NCIC 5FU/LV 292 61% 15%

Total 1027 52% 16%

Sargent ASCO 2008

DFS/OS in Stage II dMMR Patients(N=102)

DFS/OS in Stage II dMMR Patients(N=102)

HR: 2.80 (0.98-8.97)p=0.05

5-yr DFS

Untreated 87%Treated 72%

Sargent ASCO 2008

HR: 3.15 (1.07-9.29)p=0.03

Untreated 93%Treated 75%

5-yr OSN = 55N = 47

PETACC 3: Stage-Specific Prognostic Values

PETACC 3: Stage-Specific Prognostic Values

Roth AD, et al. ASCO 2009.

MarkerStage II (n=420) Stage III (n=984)

HR P HR P

MSI (Hi vs Stable) 0.3 0.004 0.7 0.06

18qLOH 2.1 0.03 1 0.91

SMAD4 (any loss) 1.4 0.21 1.6 <0.0001

hTERT (High) 1.4 0.32 1.5 0.01

p53 (High) 1.0 0.98 1.3 0.03

TS (High) 0.5 0.03 0.7 0.02

KRAS (Mutated) 1.1 0.84 1.0 0.72

BRAF(Mutated) 0.9 0.90 1.2 0.28

P values from the Wald test in a univariate Cox regressionHR = hazard ratio

PETACC 3: Multivariate Analysis Stage II

PETACC 3: Multivariate Analysis Stage II

Roth AD, et al. ASCO 2009.

Markers HR [95% CI] P value

T4 v. T3 2.58 [1.56 - 4.28] 0.00024

MSI-H v. MSS 0.28 [0.10 - 0.72] 0.0089

18qLOH 1.37 [0.67 - 2.77] 0.38

9385

72

83

64

44

8

Per

cen

tag

e o

f P

atie

nts

(%

)

p < .001

010

2030

4050

6070

8090

100

Stage I StageIIA

StageIIB

StageIIIA

StageIIIB

StageIIIC

Stage IV

O’Connell et al., 2004.

(T3N0)(T1–2N0) (T4N0) (T1–2N1) (T3–4N1) (TanyN2) (M1)

5-Year Relative SurvivalBy AJCC Stage

5-Year Relative SurvivalBy AJCC Stage

• MSI as a suppressor of lymph node and distant metastasis?

• MSI as a suppressor of lymph node and distant metastasis?

*Br J Cancer. 2009 100(2):266-73.

Frequency Analysis

Stage II Stage III Stage IV

MSI-H 22%

(86/395)

12%

(104/859)

3.5% *

PETACC 3: Detailed Analysis of MSIPETACC 3: Detailed Analysis of MSI

Tejpar, et al. ASCO 2009. (abstract 4001)

HR MSI H (95% CI)

5FU(n= 625)

5FU/iri(n= 608)

Both arms

Stage II

(n= 391)

RFS 0.228 (0.05-0.955)P= 0.043

0.296 (0.091-0.968)P=0.044

0.265(0.107- 0.661)P= 0.0044

OS 0.18 (0.02-1.34) P= 0.095

0.143 (0.02-1.06)P=0.057

0.159( 0.039- 0.659)P=0.011

Stage III

(n= 842)

RFS 0.596 (0.344-1.03) P=0.064

0.815 (0.478-1.39)P=0.45

0.693 (0.473-1.02)P= 0.06

OS 0.515 (0.261-1.02) P=0.055

0.939 (0.515-1.71) P=0.84

0.699 (0.446- 1.09 )P= 0.12

Both stages

* P are stage corrected

RFS 0.501 (0.300-0.837)P=0.0083

0.642 (0.394-1.05)P=0.076

0.569 ( 0.400 -0.811)P=0.0018

OS 0.437(0.229-0.833) P= 0.012

0.676 (0.380-1.20) P= 0.18

0.548 (0.357-0.842)P=0.006

Results: Prognostic impact of MSI

Tejpar, et al. ASCO 2009. (abstract 4001)

Colon Cancer Technical Feasibility

Development StudiesSurgery Alone

NSABP C-01/C-02 (n=270)

CCF (n = 765)

Selection of Final Gene List & Algorithm

Development Studies Surgery + 5FU/LV

NSABP C-04 (n=308)

NSABP C-06 (n=508)

Clinical Validation Study – Stage II Colon Cancer

QUASAR (n>1200)

Test prognostic, but not predictive!

Development and Validation of an 18-Gene RT-PCR Colon Cancer Assay

Development and Validation of an 18-Gene RT-PCR Colon Cancer Assay

Validation of Analytical Methods

761 genes

375 genes

18 genes

ASCO 2009

Kerr et al., ASCO 2009, abstr. 4000

% o

f P

atie

nts

QUASAR: OS in patients with “no clear indication for chemo” (mostly stage II)

5-FU/LV vs surgery alone

QUASAR: OS in patients with “no clear indication for chemo” (mostly stage II)

5-FU/LV vs surgery alone

P = .025-year OS, Observation = 77.4% vs Chemotherapy = 80.3%Relative risk = 0.83 (95% CI, 0.71-0.97)

Years

QUASAR group, Lancet 2007

0 1 2 3 4 5 6 7 8 9 100

20

40

60

80

100Observation (n=1622)

Chemotherapy (n=1617)

5-yr OS difference: 2.9%

QUASAR: Evaluable Stage II Colon Cancer Patients

Parent QUASAR studyn=3,239

Patients with collected blocksn=2,197 (68%)

Confirmed stage IIn=1,490 (69%)

Final evaluable populationn=1,436

54 excluded (3.6%):29 synchronous tumors

8 insufficient tissue7 identifier queries

6 RNA quality/quantity4 ineligible histology

707 cases stage III and rectal cancer


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


22% (16%-29%)

18% (13%-24%)

12% ( 9% -16%)

Kaplan-Meier Estimates (95% CI) of Recurrence Risk at 3 years

QUASAR Results: Recurrence Risk in Pre-specified Recurrence Risk Groups (n=711)

Comparison of High vs. Low Recurrence Risk Groups

using Cox Model: HR = 1.47 (p=0.046) Years

Recurrence Risk Group

High

Intermediate

Low

Pro

po

rtio

n E

ven

t F

ree

0.0

0.2

0.4

0.6

0.8

1.0

0 1 2 3 4 5

Recurrence Risk Group

Range of RS

Proportion of patients

Low <30 43.7%

Intermediate 30-40 30.7%

High ≥41 25.6%


QUASAR Results: Prediction of Differential 5FU/LV Benefit for Treatment Score

• Continuous Treatment Score and Treatment Benefit with 5FU/LV – Treatment Score by Treatment Interaction for RFI:

interaction p = 0.19

• Selected Secondary Analyses– Treatment Score by Treatment Interaction not

significant when adjusted for prognostic covariates

– Treatment Score by Treatment Interaction not significant for DFS (interaction p=0.12) or OS (interaction p=0.15)


QUASAR RESULTS: Recurrence Score, T Stage, and MMR Deficiency are Key Independent Predictors of Recurrence

in Stage II Colon Cancer

QUASAR RESULTS: Recurrence Score, T Stage, and MMR Deficiency are Key Independent Predictors of Recurrence

in Stage II Colon Cancer

Multivariate AnalysisKerr et al., ASCO 2009, abstr. 4000

QUASAR Results: Recurrence Score, T Stage, and MMR Deficiency are Key

Independent Predictors of Recurrence in Stage II Colon Cancer

0%

5%

10%

15%

20%

25%

30%

35%

40%

45%

0 10 20 30 40 50 60 70

Recurrence Score

Ris

k o

f re

curr

en

ce

at

3 y

ears

T3 and MMR deficient (11%)

T4 stage (13%)

T3 and MMR proficient (76%)


Decision Algorithm in Adjuvant TherapyDecision Algorithm in Adjuvant Therapy

Resected Colon Ca

Stage II Stage III

FOLFOX

High-Risk

dMMR

No therapy!5-FU/LV or

Capecitabine*

*

*pts not considered candidates for oxaliplatin

T4 and/or<12 LNs

Low-Risk

Intermed. Risk

yes

yes

no

no

?OncotypeColon ?

Neo-Adjuvant Therapy of Rectal Cancer

Neo-Adjuvant Therapy of Rectal Cancer

• 4007 ACCORD-2 Gerard

• 4008 STAR Aschele

• 4014 AIO Hofheinz

• 4007 ACCORD-2 Gerard

• 4008 STAR Aschele

• 4014 AIO Hofheinz

Addition of Oxaliplatin to Fluoropyrimidine-based Neoadjuvant

Radio-Chemotherapy

Addition of Oxaliplatin to Fluoropyrimidine-based Neoadjuvant

Radio-Chemotherapy

• Locally advanced rectal cancer• High rates of distant metastases (30-35%)• Positive circumferential resection margin in

10-30% of “resectable” tumors

• Oxaliplatin • Improves the efficacy of FU-based

chemotherapy • Radiosensitizing properties in experimental

models• Promising activity with preoperative

radiotherapy and fluorouracil

• Locally advanced rectal cancer• High rates of distant metastases (30-35%)• Positive circumferential resection margin in

10-30% of “resectable” tumors

• Oxaliplatin • Improves the efficacy of FU-based

chemotherapy • Radiosensitizing properties in experimental

models• Promising activity with preoperative

radiotherapy and fluorouracil

Aschele. ASCO 2009. Abstract CRA4008.

Oxaliplatin in Neoadjuvant Radio-Chemotherapy for Rectal CancerOxaliplatin in Neoadjuvant Radio-Chemotherapy for Rectal Cancer

Author N Chemo RTGrade 3-4 toxicity

Pathological CR rate

Aschele

(STAR)

379 5-FU 225 mg/m2/d50.4 Gy in

28 fractions 8% 16%

368

5-FU 225 mg/m2/d

Oxaliplatin 60 mg/m2/w x 6

50.4 Gy in 28 fractions 24% 15%

Gerard

(ACCORD)

295Capecitabine 800 mg/m2 bid

45 Gy in 25 fractions 11% 14%

292

Capecitabine 800 mg/m2 bid 5 of 7 d

Oxaliplatin 50 mg/m2/w

50 Gy in 25 fractions 25% 19%

Aschele. ASCO 2009. Abstract CRA4008. Gerard. ASCO 2009; Abstract LBA4007.

Log-rank: p=0.303

AIO Study – Rtx + Cape or 5-FU: Disease free survival

Preliminary data

Hofheinz. ASCO 2009. Abstract 4014.

50.4 Gy + N Pts197195

Median follow-up: 1.6 years

Neoadjuvant Therapy of Rectal Cancer – ASCO 2009

Neoadjuvant Therapy of Rectal Cancer – ASCO 2009

• Capecitabine had activity similar to 5-FU

• Addition of oxaliplatin did not improve response• Increased toxicity• Oxaliplatin does not appear to be a

radiosensitizer in these studies

• Implications for ongoing NSABP R-04?• Cape vs ci 5-FU +/- oxaliplatin plus Rtx• Primary EP: local disease control• Accrual: 1260/1600 pts

• Capecitabine had activity similar to 5-FU

• Addition of oxaliplatin did not improve response• Increased toxicity• Oxaliplatin does not appear to be a

radiosensitizer in these studies

• Implications for ongoing NSABP R-04?• Cape vs ci 5-FU +/- oxaliplatin plus Rtx• Primary EP: local disease control• Accrual: 1260/1600 pts

Other GI MalignanciesOther GI Malignancies

• 4503 GemCis Biliary Valle

• 4505 ESPAC-3Neoptolemos

• 4506 LMWH in PC Riess

• 4509 ToGA Van Cutsem

• 4503 GemCis Biliary Valle

• 4505 ESPAC-3Neoptolemos

• 4506 LMWH in PC Riess

• 4509 ToGA Van Cutsem

Trastuzumab plus Chemotherapy in Advanced HER2+ Gastric Cancer: ToGA

Trastuzumab plus Chemotherapy in Advanced HER2+ Gastric Cancer: ToGA

Van Cutsem et al. J Clin Oncol 2009; 27(suppl):798s (LBA4509)

Bang et al. J Clin Oncol 2009; 27(suppl): 215s (abstract 4556)

Van Cutsem et al. J Clin Oncol 2009; 27(suppl):798s (LBA4509)

Bang et al. J Clin Oncol 2009; 27(suppl): 215s (abstract 4556)

Rationale: A subpopulation of gastric cancers overexpress HER2Rationale: A subpopulation of gastric cancers overexpress HER2

Stratification by•Gastric vs GEJ

•Advanced vs metastatic•5-FU vs capecitabine 5-FU 800 mg/m2/d infusional d1-5 q3w X 6

Capecitabine 1000 mg/m2 bid d1-14 q3w X 6Cisplatin 80 mg/m2 q3w X 6

Trastuzumab 6 mg/kg q3w to PD (8 mg/kg loading)

5-FU or Capecitabine (investigator discretion)

+ Cisplatin + Trastuzumab (n=294)

5-FU or Capecitabine (investigator discretion)

+ Cisplatin(n=290)

(n = 584)

HER2+ GC(n = 810,

22%)R

Screen 3807 GC patients

for HER2 expression

Primary endpoint: OS

ToGA: Main patient selection criteriaToGA: Main patient selection criteria

Exclusion criteria

• Previous adjuvant chemotherapy within 6 months • Chemotherapy for advanced disease• Congestive heart failure or baseline LVEF <50%• Creatinine clearance <60 mL/min

Exclusion criteria

• Previous adjuvant chemotherapy within 6 months • Chemotherapy for advanced disease• Congestive heart failure or baseline LVEF <50%• Creatinine clearance <60 mL/min

IHC, immunohistochemistry; FISH, fluorescence in situ hybridization; LVEF, left ventricular ejection fraction

Inclusion criteria

• Adenocarcinoma of stomach or GEJ• Inoperable locally advanced and/or metastatic disease• Measurable (RECIST), or non-measurable evaluable disease• HER2-positive tumor (centrally assessed)

– IHC 3+ and/or FISH+• Adequate organ function and ECOG performance status ≤2• Written informed consent

Inclusion criteria

• Adenocarcinoma of stomach or GEJ• Inoperable locally advanced and/or metastatic disease• Measurable (RECIST), or non-measurable evaluable disease• HER2-positive tumor (centrally assessed)

– IHC 3+ and/or FISH+• Adequate organ function and ECOG performance status ≤2• Written informed consent

Van Cutsem et al. ASCO 2009 (LBA4509)Van Cutsem et al. ASCO 2009 (LBA4509)

Patient demographics and baseline characteristics

Patient demographics and baseline characteristics

Characteristic F+Cn=290

F+C + trastuzumabn=294

Sex, %Male / Female 75 / 25 77 / 23

Age, median (range) years 59.0 (21-82) 61.0 (23-83)

Weight, median (range) kg 60.3 (28-105) 61.5 (35-110)

Region, n (%)AsiaC/S AmericaEuropeOther

166 (56)26 (9)

95 (32)9 (3)

158 (53)27 (9)

99 (33)14 (5)

Type of GC (central assessment)IntestinalDiffuseMixed

74.2a

8.7a

17.1a

76.8b

8.9b

14.3b

Prior gastrectomy 21.4 24.1

Highest recruitment was from Korea, Japan, China and Russia F, fluoropyrimidine; C, cisplatin an=287; bn=293 Van Cutsem et al. ASCO 2009 (LBA4509)Van Cutsem et al. ASCO 2009 (LBA4509)

Events

167182

ToGA: Primary end point: OSToGA: Primary end point: OS

Time (months)

294290

277266

246223

209185

173143

147117

11390

9064

7147

5632

4324

3016

2114

137

126

65

40

10

00

No. at

risk

11.1 13.8

0.00.10.20.30.40.50.60.70.80.91.0

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36

Event

FC + TFC

HR

0.74

95% CI

0.60, 0.91

p value

0.0046

MedianOS

13.811.1

T, trastuzumab Van Cutsem et al. ASCO 2009 (LBA4509)Van Cutsem et al. ASCO 2009 (LBA4509)

Events

226235

ToGA: Secondary end point: PFSToGA: Secondary end point: PFS

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34

Event

294290

258238

201182

14199

9562

6033

4117

287

215

133

93

82

62

61

61

40

20

00

5.5 6.7

No. at risk

0.00.10.20.30.40.50.60.70.80.91.0

Time (months)

FC + TFC

HR

0.71

95% CI

0.59, 0.85

p value

0.0002

MedianPFS

6.75.5


ToGA: Efficacy: OS by HER2 status

Subgroup Median OS (months)

All 11.1 13.8vs

Pre-planned analysis

IHC0/FISH+

IHC1+/FISH+

IHC2+/FISH+

IHC3+/FISH+

IHC3+/FISH-

7.2

10.2

10.8

12.3

17.7

10.6

8.7

12.3

17.9

17.5

Exploratory analysis

IHC0 or 1+/FISH+

IHC2+/FISH+ or IHC3+

8.7

11.8

10.0

16.0

vs

vs

0.2 0.4 0.6 1 2 3 4 5

vs

vs

vs

vs

vs

0.92

1.24

0.75

0.58

0.83

0.48, 1.76

0.70, 2.20

0.51, 1.11

0.41, 0.81

0.20, 3.38

Hazardratio

95% CI

0.74 0.60, 0.91

1.07

0.65

0.70, 1.62

0.51, 0.83

Risk ratioFavors T Favors no T

584

61

70

159

256

15

131

446

N


113

ToGA: OS in IHC2+/FISH+ or IHC3+ (exploratory analysis)

ToGA: OS in IHC2+/FISH+ or IHC3+ (exploratory analysis)

1.0

0.8

0.6

0.4

0.2

0.0

363432302826242220181614121086420

Time (months)

11.8 16.0

FC + T

FC

Events

120136

HR

0.65

95% CI

0.51, 0.83

MedianOS

16.011.8

Event

0.1

0.3

0.5

0.7

0.9

218 198

40

53

124

2011

228 218

196 170

170 141

142 112

12296

10075

8453

6539

5128

10

00

No. at

risk

3920

2813


ToGA: Efficacy OutcomeToGA: Efficacy Outcome

Fluoropyrimidine + Cisplatin + Trastuzumab

(n = 294)

Fluoropyrimidine + Cisplatin(n = 290)

HR [95% CI] P Value

OS 13.8 months 11.1 months 0.74 [0.60-0.91] .0046

PFS 6.7 months 5.5 months 0.71 [0.59-0.85] .0002

ORR 47% 34.5% .0017

CR 5% 2% .0599

PR 42% 32% .0145

• Preplanned subgroup analysis indicated improved OS benefit with increasing HER2 expression by IHC

• Exploratory analysis of IHC2+/FISH+ and IHC3+ cohort demonstrated a4 month increase in OS with trastuzumab (HR [95% CI], 0.65 [0.51-0.83])


ToGA: Select Grade 3/4 Toxicities*ToGA: Select Grade 3/4 Toxicities*


Fluoropyrimidine + Cisplatin +

Trastuzumab(n = 294)

Fluoropyrimidine + Cisplatin(n = 290)

Hematologic

Neutropenia 27% 30%

Anemia 12% 10%

Nonhematologic

Diarrhea 9% 4%

Nausea 7% 7%

Asymptomatic LVEF drops (< 50%)

6% 1%

*2 deaths due to cardiac events in each arm

Gemcitabine ± Cisplatin in Advanced Biliary Tract Cancer: Phase III UK ABC-02 Trial

Gemcitabine ± Cisplatin in Advanced Biliary Tract Cancer: Phase III UK ABC-02 Trial

• Primary endpoint: OS

• Secondary endpoints including: PFS, toxicity

• Primary endpoint: OS

• Secondary endpoints including: PFS, toxicity

Eligibility criteria:•No prior systemic therapy•Adequate biliary drainage

Stratification by

•Site of primary•LA vs metastatic•Prior therapy

Cisplatin 25 mg/m2

+ Gemcitabine 1000 mg/m2

d 1, 8 q21d for 8 cycles(n=204)

Gemcitabine 1000 mg/m2 d 1, 8, 15 q28d for 6 cycles

(n=206)

(n = 410)

RANDOMIZE

Valle et al. ASCO 2009 (abstract 4503) Valle et al. ASCO 2009 (abstract 4503)

UK ABC-02 Trial: Select Grade 3/4 Adverse Events

UK ABC-02 Trial: Select Grade 3/4 Adverse Events


Gem + Cis(n = 159)

Gem(n = 165)

Hematologic

Neutropenia 36 (23%) 29 (18%)

Leukopenia 24 (15%) 18 (11%)

Nonhematologic

Any 102 (64%) 108 (65.5%)

Elevated Bilirubin 17 (11%) 21 (13%)

Elevated ALT 15 (10%) 28 (18%)

Elevated AST 12 (8%) 17 (11%)

Fatigue 29 (19%) 27 (17%)

No significant differences between arms

UK ABC-02 Trial: EfficacyUK ABC-02 Trial: Efficacy

Gemcitabine + Cisplatin(n = 148)

Gemcitabine(n = 132)

P Value(HR [95%CI])

ORR 38 (26%) 21 (16%) NR

CR 1 (< 1%) 1 (< 1%) NR

PR 37 (25%) 20 (15%) NR

SD 79 (53%) 73 (55%) NR

CBR (CR + PR +SD) 117 (79%) 94 (71%) .256

(n = 204) (n = 206)

PFS 8.4 months 6.5 months.003

(0.72 [0.57-0.90])

OS 11.7 months 8.3 months.002

(0.70 [0.54-0.89])


ABC-02 Results: Progression-free survival (ITT)

Treatment arm Gem Gem + Cis

Number of patients n=206 n=204

PFS events n(%) 155 (75.2) 135 (66.2)

Median PFS (mo) 6.5 8.4

Log rank p value 0.003

Hazard ratio (95% CI) 0.72 (0.57, 0.90)


ABC-02 - Results: Overall Survival (ITT)

Treatment arm Gem Gem + Cis

Number of patients n=206 n=204

Deaths n(%)141

(68.5) 122 (59.8)

Median survival (mo) 8.3 11.7

Log rank p value 0.002

Hazard ratio (95% CI) 0.70 (0.54, 0.89)


ABC-02 - Overall Survival Exploratory sub-group

analysis

ABC-02 - Overall Survival Exploratory sub-group

analysis


CONKO-001 Gemcitabine as Adjuvant Therapy in Resected PC

CONKO-001 Gemcitabine as Adjuvant Therapy in Resected PC

Gem

Obs

Gemcitabine 1000 mg/m²: d1, 8, 15; q 4 weeks

Observation: d1; q 4 weeks

Randomization

Follow up every 8weeks

Gem

Ultrasoundafter week 8

Ultrasoundafter week 16

CT Scanafter week 32

Obs

Gem

Obs

Gem

Obs

Gem

Obs

Gem

Obs

Gem

Obs

CA 19-9 CA 19-9 CA 19-9 CA 19-9 CA 19-9 CA 19-9

4 weeks 4 weeks 4 weeks 4 weeks 4 weeks 4 weeks

CA 19-9

Oettle et al., JAMA 2007

CONKO-001 ASCO 2008 UpdateCONKO-001 ASCO 2008 Update

Neuhaus et al., ASCO 2008

months

847260483624120

cum

ula

tive

su

rviv

al

100%

75%

50%

25%

0%

Gemcitabine

mOS: 22.8 mos (95% CI, 18.5-27.2)

Observation

mOS: 20.2 mos (95% CI, 17.7-22.8)

P = 0.005

OS Rate (%)

Obs GEM

1yr 72.5 72.0

3yrs 19.5 36.5

5yrs 9.0 21.0

ESPAC-3: Adjuvant bolus 5-FU/LV vs Gemcitabine in Pancreatic Cancer

ESPAC-3: Adjuvant bolus 5-FU/LV vs Gemcitabine in Pancreatic Cancer

Neoptolemos et al. ASCO 2009 (abstract 4505) Neoptolemos et al. ASCO 2009 (abstract 4505)

CONKO-4: LMWH vs Observation in metastatic PC

CONKO-4: LMWH vs Observation in metastatic PC

Riess et al. ASCO 2009 (abstract 4506) Riess et al. ASCO 2009 (abstract 4506)

CONKO-4: LMWH vs Obs. in mPCCONKO-4: LMWH vs Obs. in mPC

Riess et al. ASCO 2009 (abstract 4506) Riess et al. ASCO 2009 (abstract 4506)

asco 2009 highlights in gastrointestinal malignancies axel grothey professor of oncology mayo clinic...

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