1. Risk Stratified Analysis Improves Prediction of Treatment Benefit Over Subgroup Analysis: Findings from Intergroup N9741 HK Sanoff, ME Campbell, HC Pitot, RM Goldberg, DJ Sargent University of North Carolina at Chapel Hill, and Mayo Clinic for the NCCTG, CALGB, ECOG, SWOG, NCIC ABSTRACT # 4018

2. Despite recent advances in therapy for metastatic colorectal cancer (MCRC), individuals’ responses to treatment and clinical courses remain heterogeneous. Despite recent advances in therapy for metastatic colorectal cancer (MCRC), individuals’ responses to treatment and clinical courses remain heterogeneous. A substantial minority of patients progress rapidly, dying of disease within a year of diagnosis. A substantial minority of patients progress rapidly, dying of disease within a year of diagnosis. Several baseline factors indicate a poor prognosis, i.e.: Several baseline factors indicate a poor prognosis, i.e.: –Performance status (PS) > 2 –Alkaline phosphatase (ALK) > twice upper limit of normal. No baseline factors currently are used in treatment selection No baseline factors currently are used in treatment selection BACKGROUND

3. Risk stratified analysis (RSA) assesses treatment effect according to baseline risk Risk stratified analysis (RSA) assesses treatment effect according to baseline risk –Uses pre-existing risk models to divide patients into risk groups. –Outcomes stratified based on these risk groups RSA advocated as a better method for predicting patient specific treatment benefit over subgroup analysis. RSA advocated as a better method for predicting patient specific treatment benefit over subgroup analysis. –RSA does not artificially divide according to one factor when many may coexist within one patient. BACKGROUND Risk Stratified Analysis Kent & Hayward, JAMA 2007; 298: 1209

4. Perform RSA of a large, phase III trial of first-line chemotherapy for MCRC Perform RSA of a large, phase III trial of first-line chemotherapy for MCRC Compare RSA to subgroup analysis by PS Compare RSA to subgroup analysis by PS Assess for differences in treatment benefit by risk group Assess for differences in treatment benefit by risk group OBJECTIVES

5. Individual patient data from N9741, Phase III trial of FOLFOX vs. IROX vs. IFL Individual patient data from N9741, Phase III trial of FOLFOX vs. IROX vs. IFLN=1682 RSA based on risk model of Köhne et al. RSA based on risk model of Köhne et al. Köhne model developed in patients with MCRC treated with 5FU. 3 risk groups based on: Köhne model developed in patients with MCRC treated with 5FU. 3 risk groups based on: – ECOG PS – WBC – Alkaline phosphatase – Number of sites of metastatic disease METHODS Köhne Köhne et al. Ann Oncol 2002; 13: 308.

6. METHODS RISK GROUPS: RISK GROUPS: OS and TTP were compared by risk group, PS. OS and TTP were compared by risk group, PS. Cox models assessed the relative predictive utility of PS and risk group. Cox models assessed the relative predictive utility of PS and risk group. *WBC estimated from absolute granulocyte count (AGC) based on AGC= -0.7 + 0.8(WBC) [Benson, Cancer 1985].

7. RESULTS Overall survival by Risk Group

8. RESULTS Overall survival by Performance Status

9. RESULTS: OS Multivariate model Prediction improved by PS and Risk Group Risk Group HR (95% CI) X2X2X2X2P-Value PS 0 1 PS 1 1.4 (1.3, 1.6) 41.0<0.0001 PS 2 1.5 (1.2, 2.0) 10.30.0014 Low 1 Intermediate 1.4 (1.2, 1.5) 31.7<0.0001 High 2.3 (1.9, 2.8) 71.6<0.0001 Likelihood Ratio X2 for PS = 83.8, for Kohne = 114.1, Combined Model=157.6

10. RESULTS OS by treatment arm, risk group Risk Group Trt Arm N Median (Months) HR (95% CI) P-Value Low FOLFOX24727.51 IFL14618.2 1.7 (1.4, 2.1) <0.001 IROX13519.7 1.5 ( 12, 1.8) <0.001 Intermediate FOLFOX38419.21 IFL22713.8 1.5 (1.3, 1.8) <0.001 IROX19617.8 1.3 (1.1, 1.6) 0.005 High FOLFOX6010.71 IFL559.4 1.3 (0.87, 1.9) 0.21 IROX499.1 0.22 Interaction p value risk group X treatment arm=0.08

11. CONCLUSIONS RSA using the Köhne model is prognostic of survival in this cohort treated with combination chemotherapy. RSA using the Köhne model is prognostic of survival in this cohort treated with combination chemotherapy. FOLFOX is superior to IFL in all risk groups. FOLFOX is superior to IFL in all risk groups. Trend towards less benefit in high risk group. Trend towards less benefit in high risk group. –Small # high risk patients supports need for pooled analyses of these patients.

12. CONCLUSIONS RSA adds predictive ability to a multivariate model above PS alone. RSA adds predictive ability to a multivariate model above PS alone. RSA should be considered as a way to present clinical trial data to better inform pts and physicians of treatment benefit RSA should be considered as a way to present clinical trial data to better inform pts and physicians of treatment benefit RSA is useful for designing clinical trials to ensure balanced randomization RSA is useful for designing clinical trials to ensure balanced randomization