Biomarker-driven treatment decisions in stage II colon cancer -

making sense of what we know

June 7, 2010

Neal J. Meropol, M.D.Chief, Division of Hematology and Oncology

University Hospitals Case Medical CenterAssociate Director for Clinical Research

Case Comprehensive Cancer CenterCase Western Reserve University

Cleveland, Ohio

QUASAR

Survival – Stage II (92% of patients enrolled, N=2963)

QUASAR Collaborative Group, Lancet, 2007

RR=0.84P=0.05

Sargent, D. et al. J Clin Oncol; 2009

N = ~70005% benefit at 8

years

ACCENT pooled analysis: benefit of adjuvant therapy in stage II colon cancer

The Data

• Not all patients with stage II colon cancer have the same risk

• In unselected patients– 5-FU improves survival by a few percent– Oxaliplatin does not improve survival– Capecitabine as effective as 5-FU

• Clinical risk factors include– T4, obstruction, lymphovascular invasion,

lymph node retrieval

Risk stratificationis critical to decision making

in stage II colon cancer

• Predictive: explains variability in response to treatment

• Prognostic: explains variability irrespective of treatment

Variability exists in the host (germline) and tumor (somatic)

A Common Assumption

The risk reduction associated with adjuvant therapy is consistent across

the spectrum of risk

Risk

Relapse

No Rx

Adj Rx

The use of adjuvant therapy for stage II colon cancer requires a

decision on the part of physicians and patients

What makes a good decision?

• Adequate understanding of alternatives• Adequate understanding of potential risks

and benefits• Freedom from coercion• “Rational” weighing of risks and benefits

– consonant with individual values and preferences

– “rational” does not imply that we would make the same decision

• Results in satisfaction

How do patients weigh decisions?

• Side effects

- Intensity

- Duration• Cost• Inconvenience

• Delay recurrence

• Reduce recurrence

What are the key issues?

• Potential benefit• Potential harm

–Short-term–Long-term

• Patient preferences

Should baseline risk make a difference?

Only if risk reduction is proportionate to absolute risk level

Decision making considerations

Relative vs. Absolute Risk Reduction

100

50

75

25

Su

rviv

al %

Time

5%RRR = 25%ARR = 5%

“I can improve your chances by 5%”“I can reduce your risk by 25%”

“I have to treat 100 people like you to save 5”

Patients are not MathematiciansWeinfurt et al. Cancer 2003

The following question involves a hypothetical situation in which your doctor is describing a new treatment. Imagine that your doctor says this new

treatment controls cancer in 40% of cases like yours. How do you interpret what the doctor is

saying?

14% The doctor is 40% confident that the treatment will control my cancer.

72% For every 100 patients like me, the treatment will work for 40 patients.

3% The new treatment will reduce my disease by 40%.4% I am not sure what this information means.3% Other5% Don’t know/unsure

What is Rational?

Or

What is the minimum absolute benefit that you would require to

feel comfortable offering (or receiving) adjuvant therapy?

Weinfurt, K. P. J Clin Oncol; 25:223-227 2007

Prospect Theory: People Care More About Outcomes Close to Their

Reference Point

Weinfurt, K. P. J Clin Oncol; 25:223-227 2007

Prospect Theory: People Care More About Loss Than Gain

Shifting Reference

Point

People weight probabilities differently depending on where they fall on the probability curve

• The “Russian Roulette” experiment (Zeckhauser; Kahneman and Tversky)– You’d pay more to remove 1 bullet if the chamber

is full, than if it only has 3 or 4 bullets to begin– You’d pay more to remove the final bullet, than to

remove 1 bullet from a chamber with 3 or 4 bullets

Do patients with stage II colon cancer weight absolute benefits of adjuvant therapy differently based upon their

baseline underlying risk of recurrence?

Age may be an appropriate consideration

%AC85%52%35%

Earle et al. J Surg Oncol, 2009

Should age matter?

ACCENT: No benefit for combinations on survival in elderly (stage II/III)

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 et al. ASCO 2009

Molecular Risk Stratification• Mismatch repair is ready for clinical use

– MSI vs. IHC– Prognostic and ?predictive– Implications for hereditary predisposition

• Oncotype DX is a validated platform – Establishes prognosis– Relative benefit of 5-FU is consistent

across risk spectrum– Does not address benefit of oxaliplatin– Peer-reviewed publication is awaited

• ?Other molecular risk classifiers

Classifier discovery and validation

Discovery Validation

• assay technology• patient population

characterized• samples representative• training and validation sets

• Prospective randomized trial is gold standard

• Retrospective randomized trial may be acceptable if:– a priori hypothesis and

statistical design– samples available from

vast majority of patients– adequate follow up and

annotation

Adapted from D. Sargent, ISGIO 9/07

QUASAR Recurrence Score

• 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

• The relative risk reduction with 5-FU is consistent across Recurrence Score risk levels

STROMALFAP

INHBABGN

CELL CYCLEKi-67

C-MYCMYBL2

REFERENCEATP5EGPX1PGK1UBB

VDAC2

GADD45B

RECURRENCE SCORECalculated from Tumor

Gene Expression

Kerr et al. ASCO 2009

QUASAR : Clinical/Pathological Covariates and Recurrence

Variable Categories HR HR

95% CI P value

Mismatch Repair (MMR) 13% Deficient vs. 87% Proficient 0.32 (0.15,0.69) <.001

T Stage 15% T4 vs. 85% T3 1.83 (1.23,2.75) 0.005

Tumor Grade 29% High vs. 71% Low 0.62 (0.40,0.96) 0.026

Number of Nodes Examined 62% <12 vs. 38% ≥12 1.47 (1.01,2.14) 0.040

Lympho-Vascular Invasion 13% Present vs. 87% Absent 1.40 (0.88,2.23) 0.175

Recurrence Score continuous per 25 units 1.61 (1.13,2.29) 0.008

Pre-specified Multivariate Analysis, Surgery Alone Patients (n=605)

Kerr et al. ASCO 2009

QUASAR Results: Colon Cancer Recurrence Score Predicts Recurrence Following

Surgery

Ris

k of

Rec

urre

nce

at 3

yea

rs

0%

5%

10%

15%

20%

25%

30%

35%

Recurrence Score0 10 20 30 40 50 60 70

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

Kerr et al. ASCO 2009

Recurrence Score, T Stage, and MMR Deficiency are 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

ence

at

3 ye

ars

MMR deficient (11%)

T4 stage (13%)

T3 and MMR proficient (76%)

Kerr et al. ASCO 2009

E5202: Stage II Colon Cancer

Accrual Goal: 3438

Arm A:FOLFOX

Arm B:FOLFOX + Bevacizumab

Tumor block risk

assessment based on biology

(18q/MSI)

High-risk (MSS and 18q LOH)

Low-risk (MSI + or no

loss 18q)Observation

Surgery

NCCN Recommendations 2010

• Ask the patient how much they’d like to know• Discuss risks and benefits• Consider clinical features that confer risk• Consider comorbidities and life expectancy• If considering fluoropyrimidine alone, MMR

testing recommended

Proposed Stage II Algorithm Today

MMR

Clinical Risk

No Adjuvant

Deficient Intact

Not HighHigh

No AdjuvantOr

Adjuvant

Adjuvant

*all decisions require discussion with patient

Proposed Stage II Algorithm Soon

MMR

Clinical & Molecular

Risk

No Adjuvant

Deficient

Intact

Very small benefit from adjuvant

therapy?<3%

No AdjuvantOr

Adjuvant

No Adjuvant

*all decisions require discussion with patient

More than very small benefit from adjuvant therapy

?3+%

What we need

• Models that integrate clinical and molecular risk assessment

• Improved methods of communicating risk (and risk reduction) to patients

• Formal modeling of impact of molecular vs. clinical tools on adjuvant therapy use, recurrence, survival, QOL, and cost

• Decision tools that go beyond simple calculations of 3 or 5 year clinical endpoints, and integrate comorbidities and life expectancy, i.e. will I gain or lose QALYs by taking adjuvant therapy?

What we needR

ecu

rren

ce R

isk

Life Expectancy

Low

High

Low High

DON’T TREAT

TREAT

?

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