1. Advanced NSCLC Objective response rate -Well defined & widely accepted -Does not correlate well with OS -May be more useful if SD included -Higher RR correlates with sx benefit Objective response rate -Well defined & widely accepted -Does not correlate well with OS -May be more useful if SD included -Higher RR correlates with sx benefit

2. Advanced NSCLC Time to tumor progression -Poorly defined, not standardized -Relationship to patient benefit is unknown -Rough correlation with OS (MST ≈ TTPx2 Time to tumor progression -Poorly defined, not standardized -Relationship to patient benefit is unknown -Rough correlation with OS (MST ≈ TTPx2

3. Advanced NSCLC Overall survival -Definitive endpoint -Most commonly used endpoint -Easily determined; hard to “fudge” -Survival benefit attributable to therapy in well designed phase III trial Overall survival -Definitive endpoint -Most commonly used endpoint -Easily determined; hard to “fudge” -Survival benefit attributable to therapy in well designed phase III trial

4. Advanced NSCLC Percent progression at defined time -Not a traditional endpoint -Association with pt benefit is unknown -Use of this endpoint implies that SD pts have a survival outcome similar to those with rumor regression -Retrospective data suggest NON-PD at a predetermined point correlates with OS Percent progression at defined time -Not a traditional endpoint -Association with pt benefit is unknown -Use of this endpoint implies that SD pts have a survival outcome similar to those with rumor regression -Retrospective data suggest NON-PD at a predetermined point correlates with OS

5. Set maximum PD rate above which agent will be rejected. PD rate of interest will vary according to tumor type. Set maximum PD rate above which agent will be rejected. PD rate of interest will vary according to tumor type. Phase II Trial Design New Paradigms for Novel Agents

6. NCIC NSCLC Trial Survival of Stable & PR vs PD

7. Treat:PD:SD:PR: E2598:5.9 mo14.6 mo17.3 mo E1594 A:5.3 mo12.7 mo14.3 mo E1594 B:5.9 mo9.7 mo16.9 mo E1594 C:5.7 mo11.3 mo18.5 mo E1594 D:5.9 mo12.8 mo14.7 mo E5592 A:5.8 mo12.4 mo15.1 mo E5592 B:5.9 mo13.2 mo15.6 mo E5592 C:5.8 mo15.9 mo11.6 mo

8. Surv:PD:SD:PR: MST:6.7 mo12.7 mo14.6 mo 1-Yr:17%53%64% 2-Yr:3%18%27% 3-Yr:1%10%12% HR:2.62-0.84 Survival Significance of SD: Landmark Analysis of E5592 & E1594:

10. Goal of phase II trial is to screen agent for efficacy. Traditionally, this is measured by objective response rate using standard criteria. ORR correlates with ‘efficacy’ (i.e. survival). Goal of phase II trial is to screen agent for efficacy. Traditionally, this is measured by objective response rate using standard criteria. ORR correlates with ‘efficacy’ (i.e. survival). Phase II Trial Design New Paradigms for Novel Agents

11. More common scenario is growth delay not tumor regression. Candidate endpoints: changes in tumor markers, target inhibition measures; PET scanning; TTP; percent early PD. None yet validated More common scenario is growth delay not tumor regression. Candidate endpoints: changes in tumor markers, target inhibition measures; PET scanning; TTP; percent early PD. None yet validated