Biomarker-driven treatment decisions in stage II colon cancer - making sense of what we know

1. Biomarker-driven treatment decisions in stage II colon cancer - making sense of what we know Neal J. Meropol, M.D. Chief, Division of Hematology and Oncology University Hospitals Case Medical Center Associate Director for Clinical Research Case Comprehensive Cancer Center Case Western Reserve University Cleveland, Ohio June 7, 2010

2. QUASAR Survival – Stage II (92% of patients enrolled, N=2963) RR=0.84 P=0.05 QUASAR Collaborative Group, Lancet, 2007

3. ACCENT pooled analysis:benefit of adjuvant therapy in stage II colon cancer N = ~7000 5% benefit at 8 years Sargent, D. et al. J ClinOncol; 2009

4. 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

5. 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)

6. A Common Assumption The risk reduction associated with adjuvant therapy is consistent across the spectrum of risk No Rx Adj Rx Risk Relapse

7. The use of adjuvant therapy for stage II colon cancer requires a decision on the part of physicians and patients

8. 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

9. How do patients weigh decisions? • Side effects • - Intensity • - Duration • Cost • Inconvenience • Delay recurrence • Reduce recurrence

10. 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

11. Decision making considerations

12. 5% Relative vs. Absolute Risk Reduction 100 Survival % 75 RRR = 25% ARR = 5% 50 “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” 25 Time

13. 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% Other 5% Don’t know/unsure

14. What is Rational?Or What is the minimum absolute benefit that you would require to feel comfortable offering (or receiving) adjuvant therapy?

15. Prospect Theory: People Care More About Outcomes Close to Their Reference Point Weinfurt, K. P. J Clin Oncol; 25:223-227 2007

16. Prospect Theory: People Care More About Loss Than Gain Shifting Reference Point Weinfurt, K. P. J Clin Oncol; 25:223-227 2007

17. 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?

18. Age may be an appropriate consideration %AC 85% 52% 35% Earle et al. J SurgOncol, 2009

19. Should age matter? ACCENT: No benefit for combinations on survival in elderly (stage II/III) McCleary et al. ASCO 2009

20. 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

21. Classifier discovery and validation • assay technology • patient population characterized • samples representative • training and validation sets Discovery Validation • 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

22. RECURRENCE SCORE Calculated from Tumor Gene Expression STROMAL FAP INHBA BGN CELL CYCLE Ki-67 C-MYC MYBL2 GADD45B REFERENCE ATP5E GPX1 PGK1 UBB VDAC2 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 Kerr et al. ASCO 2009

23. QUASAR : Clinical/Pathological Covariates and Recurrence Pre-specified Multivariate Analysis, Surgery Alone Patients (n=605) Kerr et al. ASCO 2009

24. 35% 30% 25% 20% Risk of Recurrence at 3 years 15% 10% 5% | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | 0% 0 10 20 30 40 50 60 70 Recurrence Score QUASAR Results: Colon Cancer Recurrence Score Predicts Recurrence Following Surgery Kerr et al. ASCO 2009

25. Recurrence Score, T Stage, and MMR Deficiency are Independent Predictors of Recurrence in Stage II Colon Cancer 45% T4 stage (13%) 40% 35% 30% 25% T3 and MMR proficient (76%) Risk of recurrence at 3 years 20% 15% 10% MMR deficient (11%) 5% 0% 0 10 20 30 40 50 60 70 Recurrence Score Kerr et al. ASCO 2009

26. E5202: Stage II Colon Cancer Arm A: FOLFOX Arm B: FOLFOX + Bevacizumab High-risk (MSS and 18q LOH) Tumor block risk assessment based on biology (18q/MSI) Surgery Low-risk (MSI + or no loss 18q) Observation Accrual Goal: 3438

27. 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

28. Proposed Stage II Algorithm Today MMR Deficient Intact No Adjuvant Clinical Risk High Not High Adjuvant No Adjuvant Or Adjuvant *all decisions require discussion with patient

29. Proposed Stage II Algorithm Soon MMR Deficient No Adjuvant Intact Clinical & Molecular Risk Very small benefit from adjuvant therapy ?<3% More than very small benefit from adjuvant therapy ?3+% No Adjuvant No Adjuvant Or Adjuvant *all decisions require discussion with patient

30. 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?

31. What we need Low DON’T TREAT ? Recurrence Risk TREAT High Low High Life Expectancy

32. Our new cancer hospital