ASCO 2010

Biomarker-driven Treatment in Stage II Colon Cancer:

When to Hold and When to Fold

– Overview of adjuvant clinical trials in stage II colon cancer - results, challenges, and confusion. -Al B. Benson, III, MD

– Prognostic and predictive molecular biomarkers in stage II colon cancer current evidence and future perspective. -Sabine Tejpar, MD, PhD

– Biomarker-driven treatment decisions in stage II colon cancer – making sense of what we know. -Neal J. Meropol, MD

Overview of Adjuvant Clinical Trials in Stage II Colon Cancer -

Results, Challenges, and Confusion

Al B. Benson III, MD, FACPProfessor of MedicineAssociate Director for Clinical InvestigationsRobert H. Lurie Comprehensive Cancer Centerof Northwestern University

Trends in Oncology Care

• Evidence-based practice/guidelines• Risk assessment

– Pathology– Markers

• Comparative Effectiveness Research (CER)

• Archie Chocrane identified three concepts related to the evaluation of a medical technology – efficacy, effectiveness, and efficiency:– Efficacy is the extent to which an intervention does more

good than harm under ideal circumstances (i.e., in circumstances designed to maximize the effect of the intervention and eliminate confounding factors). (“Can it work?”)

– Effectiveness is the extent to which an intervention does more good than harm when provided to real-world patients by physicians practicing in ordinary clinical settings. (“Does it work in practice?”)

– Efficiency measures the effect of an intervention in relation to the resources it consumes. (“Is it worth it?”)

Comparative Effectiveness

• Individual factors contribute to differences in clinical outcomes– Race or ethnic diversity– Co-morbidities– Drug-drug interactions– Tumor heterogeneity– Tumor genetics– Host genetics

Recurrence Risk & Treatment Benefit Markers Currently Used for Stage II Colon Cancer

Recurrence Risk• Bowel obstruction or perforation• T-Stage• # of nodes assessed• Tumor grade• Lymphatic/vascular invasion• Margin status

Treatment Benefit• None

According to current guidelines*:• Unlike in breast cancer, there are no molecular markers established in

clinical practice for stage II colon cancer• No markers in stage II colon cancer identify patients with

disproportionately high or low benefit from chemotherapy

* NCCN Clinical Practice Guidelines for Oncology: Colon Cancer v3.2009 ASCO Recommendations on Adjuvant Chemotherapy for Stage II Colon Cancer, JCO, 2004.

Category SEER SEER

TN Relative survival, 5-year (%)

SE TNM stage, 6th ed

TNM stage , 7th ed

Observed survival, 5-year (%)

SE

T1N0 97.4 0.6 I I 78.7 0.5

T2N0 96.8 0.6 I I 74.3 0.4

T3N0 87.5 0.4 IIA IIA 66.7 0.6

T4aN0 79.6 1.0 IIB IIB 60.6 0.8

T4bN0 58.4 1.3 IIB IIC 45.7 1.0

T1-2N1a 90.7 1.5 IIIA IIIA 73.7 1.2

T1-2N1b 83.0 2.0 IIIA IIIA 67.2 1.6

T1-2N2a 79.0 3.6 IIIC IIIA/IIIB 64.7 3.0

T3N1a 74.2 0.8 IIIB IIIB 58.2 0.6

T4aN1a 67.6 2.0 IIIB IIIB 52.2 1.5

Colon Cancer: Expanded Changes in AJCC Substaging for Stage II and III Based on Expanded SEER Data (con’t)

AJCC 7th edition

Colon Cancer: Expanded Changes in AJCC Substaging for Stage II and III Based on Expanded SEER Data (con’t)

Category SEER SEER

TN Relative survival, 5-year (%)

SE TNM stage, 6th ed

TNM stage , 7th ed

Observed survival, 5-year (%)

SE

T3N1b 65.3 0.8 IIIB IIIB 51.7 0.6

T1-2N2b 62.4 6.5 IIIC IIIB 51.8 5.3

T4aN1b 54.0 1.9 IIIB IIIB 42.1 1.5

T3N2a 53.4 1.0 IIIC IIIB 42.8 0.8

T4aN2a 40.9 2.1 IIIC IIIC 32.5 1.7

T3N2b 37.3 1.2 IIIC IIIC 30.4 0.9

T4bN1a 38.5 2.2 IIIB IIIC 30.6 1.8

T4bN1b 31.2 2.0 IIIB IIIC 25.4 1.6

T4bN2a 23.3 2.1 IIIC IIIC 18.3 1.6

T4aN2b 21.8 2.2 IIIC IIIC 17.5 1.7

T4bN2b 15.7 1.9 IIIC IIIC 12.9 1.5

AJCC 7th edition

Observed survival rates for 28,491 cases with adenocarcinoma of the colon

0 1 2 3 4 50

10

20

30

40

50

60

70

80

90

100

I IIA IIB IIC IIIA IIIB IIIC IV

AJCC 7th edition

Prognostic Factors in Colorectal CancerCOLLEGE OF AMERICAN PATHOLOGISTS CONSENSUS

Category I path-local extent of tumor = pT path-nodes = pN blood or lymphatic invasion post-op residual tumor = R (e.g., + margin) post-op CEA

Category IIA tumor grade radial margin status residual tumor s/p neoadjuvant tx

Estimates of 5 Year DFS (%) with Surgery Plus Adjuvant Therapy

Nodal T stage Low Grade High GradeStatus

S +AT S +AT

0 nodes T3 73 77 65 70 T4 60 66 51 57

T1-T2 62 75 53 681-4 nodes T3 49 65 38 56

T4 33 51 23 40

T1-T2 39 57 28 46> 5 nodes T3 24 43 15 32

T4 11 27 5 17

Adapted from Cill et al.. J Clin Oncol 22 :1801, 2004

Existing Tools for Selecting Stage II Patients for Treatment Are Inadequate

• Guidelines: presence of any existing risk marker categorizes patients into “higher risk” vs “standard risk” groups– No further discrimination for “standard risk” (the majority)– Not individualized or quantitative

• In the absence of established predictive markers, treatment decisions today are based on the expectation that higher risk stage II colon cancer patients derive larger absolute benefit with adjuvant chemotherapy

NCCN Clinical Practice Guidelines for Oncology: Colon Cancer v3.2009ASCO Recommendations on Adjuvant Chemotherapy for Stage II Colon Cancer, JCO, 2004.

Clinical Background• The 5 year overall survival rate for patients with stage II colon

cancer is between 75% and 80%• Defining a specific high risk group of patients with stage II

disease that may benefit from adjuvant chemotherapy remains a challenge

• Retrospective analysis of molecular prognostic factors suggest that there may be subsets of patients with stage II disease who are at higher risk of recurrence

• Prognostic markers to identify these patients have not been validated in prospective trials

• Treatment options are evolving – Role of biologics in adjuvant therapy

INT 0089

67%65%75%LDLV/LEV

63%60%77%LEV

66%63%75%HDLV

67%63%77%LDLV

All Stages 5-yr OS

Stage III 5-yr OS

Stage II 5-yr OS

Proc ASCO 17:982, 1998

Multivariate Analysis for LN Negative Patients: INT-0089

Covariate OS CSSAge .0001 .0876Sex .0704 .4283T Stage .2252 .1659Tumor Type .5440 .2108Differentiation .0711 .1941# LN Removed .0005 .0071Adj Therapy .1701 .1823

CSS= cause-specific survival

Cohort Definition

3444 resected Stage II colon cancer patients

“Usual” Risk Stage II

3151

T3N0 tumor

No obstruction

No perforation

High Risk Stage II

293

T4N0 tumor

Obstruction

Perforation

International Multicentre Pooled Analysis of Colon Cancer Trials (IMPACT)

Investigators• Gruppo Interdisciplinare Valutazione Interventi Oncologia (GIVIO)

• National Cancer Institute Canada Clinical Trials Group (NCIC-CTG)

• Fondation Francaise de Cancerologie Digestive (FFCD)

• North Central Cancer Treatment Group (NCCTG)

• University of Siena

Survival by Receipt of Chemotherapy IMPACT B2 vs. SEER-Medicare

SEER-MedicareIMPACT

Deficient Mismatch Repair as a Predictive Marker for Lack of Benefit from 5-FU

based Chemotherapy in Adjuvant Colon Cancer

DJ Sargent, S Marsoni, SN Thibodeau, R Labianca, SR Hamilton, V Torri, G Monges, C Ribic, A Grothey, S Gallinger

ASCO 2008

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%

DFS by MMR status, pooled data

0102030405060708090

100

0 1 2 3 4 5Years

% D

isea

se F

ree

0102030405060708090

100

0 1 2 3 4 5Years

% D

isea

se F

ree

HR: 0.79 (0.49-1.25)p=0.30

HR: 0.51 (0.29-0.89)p=0.009

Treated (N=512) Untreated (N=515)

dMMR 70%pMMR 67%

5 yr DFSdMMR 80%pMMR 56%

5 yr DFS

DFS in pMMR patients, Pooled data

0102030405060708090

100

0 1 2 3 4 5Years

% D

isea

se F

ree

0102030405060708090

100

0 1 2 3 4 5Years

% D

isea

se F

ree

HR: 0.84 (0.57-1.24)p=0.38

HR: 0.64 (0.48-0.84)p=0.001

Stage II (N=428) Stage III (N=434)

Untreated 72%Treated 77%

Untreated 41%Treated 58%

5 yr DFS 5 yr DFS

QUASAR: 5FU/LV Chemotherapy Benefit in the 1,436 Evaluable Stage II Colon Cancer Patients

RFI

Treatment Surgery Chemo

Pro

port

ion

Eve

nt F

ree

0.0

0.2

0.4

0.6

0.8

1.0

Years

0 1 2 3 4 5

OS

Treatment Surgery Chemo

Pro

port

ion

Eve

nt F

ree

0.0

0.2

0.4

0.6

0.8

1.0

Years

0 1 2 3 4 5

DFS

Treatment Surgery Chemo

Pro

port

ion

Eve

nt F

ree

0.0

0.2

0.4

0.6

0.8

1.0

Years

0 1 2 3 4 5

Kerr et al., ASCO 2009, #4000

RFI (recurrence-free interval) DFS (disease-free survival)

OS (Overall Survival)

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

Cancer

Variable

Key

Category HR

P

value

Mismatch Repair (MMR) by IHC Deficient (13% of pts) 0.32 <.001

T Stage T4 (15% of pts) 1.83 0.005

Tumor Grade High (29% of pts) 0.62 0.026

# Nodes Examined <12 (62% of pts) 1.47 0.040

Lymphovascular Invasion Present (13% of pts) 1.40 0.175

RS per 25 units Continuous 1.61 0.008

Multivariate Analysis

Figueredo et al, JCO 22(16), 2004

Approximate Number of Patients Needed to Detect a Realistic Treatment Benefit*

Dukes’ B Dukes’ C

No. of No. of Survival ARR Patients Survival ARR Patients

At 3 years 85% 2.5% 8,000 65% 5.2% 3,400

At 4 years 80% 3.3% 5,800 58% 6.0% 2,800

At 5 years 75% 4.0% 4,700 50% 6.6% 2,400

Abbreviation: ARR = absolute risk reduction•For 90% power of detecting the treatment benefit using two-tailed significance tests at the 5% level, assuming the true relative risk reduction is 18% for both Dukes’ B and Dukes’ C.

Buyse, Piedbois, 2001

Recent Adjuvant Colon Cancer Trials

• X-ACT

• MOSAIC

• NSABP C-07

• C89803

• PETACC 3

• ACCORD-02

•NSABP C-08

•N0147

LV

OXA

RR

MOSAIC: Treatment arms

LV5FU2

FOLFOX4: LV5FU2 + Oxaliplatin 85mg/m²

Every 2 weeks, 6 months of treatment (12 cycles)

D1D1 5FU bolus5FU bolus D2D2 5FU bolus5FU bolus

LV LV5-FU infusion* 5-FU infusion*

D1D1 5FU bolus5FU bolus D2D2 5FU bolus5FU bolus

LV LV5-FU infusion* 5-FU infusion*LV LV5-FU infusion* 5-FU infusion*

D1D1 5FU bolus5FU bolus D2D2 5FU bolus5FU bolus

LV LV5-FU infusion* 5-FU infusion*

D1D1 5FU bolus5FU bolus D2D2 5FU bolus5FU bolus

LV LV5-FU infusion* 5-FU infusion*LV LV5-FU infusion* 5-FU infusion*

Disease-free Survival: Stage II and Stage III Patients

Data cut-off: June 2006

HR [95% CI] p-value

Stage II 0.84 [0.62–1.14] 0.258

Stage III 0.78 [0.65–0.93] 0.005

FOLFOX4 stage II

LV5FU2 stage II

FOLFOX4 stage III

LV5FU2 stage III

Months

Prob

abili

ty

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 72

3.8%

7.5%

p=0.258

p=0.005

Disease-free Survival: High-risk Stage II Patients

Disease-free survival (months)

FOLFOX4 n=286

LV5FU2 n=290

Prob

abili

ty

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 72

3-year 5-year

FOLFOX4 85.4% 82.1%

LV5FU2 80.4% 74.9%

HR [95% CI]: 0.74 [0.52–1.06]

High-risk stage II- defined as at least one of the following: T4, tumor perforation, bowel obstruction, poorly differentiated tumor, venous invasion , <10 lymph nodes examined; Data cut-off: June 2006

7.2%

Exploratory analysis

Stratification:

• Stage II vs. III

• Center

RANDOMIZATION

Day 1 Day 2

FA 200 mg/m2

5-FU bolus 400 mg/m2

5-FU CI 600 mg/m2

Day 1 Day 2

Irinotecan 180 mg/m2

LV5FU2

LV5FU2 as above

F

IF

Repeat q 2 weeks

for 12 Cycles

PETACC-3 (V307)

VanCutsem PASCO 2005 abstract #8

Efficacy Data for Treated Patients Randomly Assigned to the LV5FU2 Regimen

Parameter LV5FU2 Irinotecan + LV5FU2

Relapse-free survival (stage III), risk adjusted

3 year 62.9 67.9

5 year 57.3 62.8

HR 0.84

95% CI 0.73 to 0.96

P .009

Disease-free survival (stage II)

3 year 82.5 84.6

5 year 76.9 80.9

HR 0.81

95% CI 0.61 to 1.08

P .158

Parameter LV5FU2 Irinotecan + LV5FU2

Disease-free survival (stage II and III combined)

3 year 67.1 690.

5 year 61.0 63.8

HR 0.89

95% CI 0.79 to 1.00

P .045

Overall survival (stage III)

3 year 81.5 83.3

5 year 71.3 73.6

P .094

Overall survival (stage II)

3 year 93.5 95.1

5 year 88.8 90.0

P .344

Journal of Clinical Oncology, Vol 27, No 19 (July 1), 2009: pp. 3117-3125

Copyright © American Society of Clinical Oncology

Kuebler, J. P. et al. J Clin Oncol; 25:2198-2204 2007

Fig 1. National Surgical Adjuvant Breast and Bowel Project Protocol C-07 Consolidated Standards of Reporting Trials diagram

Copyright © American Society of Clinical Oncology

Kuebler, J. P. et al. J Clin Oncol; 25:2198-2204 2007

Fig 3. Treatment hazard ratio and 95% CI for disease-free survival according to patient subsets defined by baseline prognostic factors significant in multivariate analysis

Copyright © American Society of Clinical Oncology

Kuebler, J. P. et al. J Clin Oncol; 25:2198-2204 2007

Fig 2. Kaplan-Meier estimates of disease-free survival by treatment

NSABP C-08

Stage ll + lll

mFF6+B

mFF6

Randomize

Strat: # Pos. N

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

NSABP C-08

DFS

%

Yrs

1 1.5 2 2.5 30.00

0.20

0.40

0.60

0.80

1.00

0.600000000000001

0.740000000000001

0.810.85000000000

00010.87000000000

0001

NSABP C-08 HR

0.0004

0.0040.02 0.05 0.08

Ev 3yDFSmFF6+B 40 87.4 mFF6 47 84.7

HR 0.82P 0.35

DFS Stage II

0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5

020

4060

80100

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

AVANT BO17920

Stage ll + lll

FF4+B

FF4

Randomize

Strat: # Pos. N

Xelox+B

12 ’04- 5 ‘07 N=3450

E5202 Trial Schema

Low-Risk PatientsMSS or MSI-L with

retention of 18q allelesMSI-H

Arm A:mFOLFOX6q2w × 12

Arm B:mFOLFOX6 + bevacizumab* q2w × 12

Arm C:Observation only

High-Risk PatientsMSS/18q LOH orMSI-L/18q LOH

areRANDOMIZED

MSI-L = low-level microsatellite instabilityMSI-H = high-level microsatellite instability*Bevacizumab continued for an additional 6 months

Stratify:Disease stage

(IIA or IIB)Microsatellite stability

(stable vs MSI)18q LOH