1. Which difference should we target? Alberto Sobrero Ospedale San Martino IRCCS Genova, Italy

2. Which delta should we target? Delta for deciding GO - NO GO to phase III (signal generating trials) Delta of phase III

3. Randomized Phase II R Perifosine Capecitabine Placebo Capecitabine Bendell JCO 2011 Median PFS 6 vs 2.5 mo HR: 0.25 (0.1-0.5) Median OS 17.7 vs 6.7 mo HR 0.37 (0.2-0.7)

4. Overall Survival – All Patients

5. Progression Free Survival – All Patients

6. 1Does the agent affect the natural hx of the disease ? Are we reasonably sure that the outcome would not have occurred in the absence of the investigational agent ? 2To what extent? How sure are we of the size of the activity ? 3Is this effect enough to go to Ph III ? Rationale. why should it work in this disease ? empirical, preclinical evidence PK-PD. Is optimal dose and schedule defined ? We expect too much from a Phase II

9. PFS on study vs PFS on prior regimen

10. PFS on study vs PFS on prior regimens NO

11. Which delta should we target? Delta for deciding GO - NO GO to phase III (signal generating trials) It is crucial that efficacy data from phase I-II whether comparative or non comparative be interpreted in the strictest way.

12. Size of benefit (target delta) : a compromise 1. plausible to achieve 2. worthwhile if achieved

13. 0.5means doubling of the benefit vs control 4  8 months 0.66means 50% increment of the benefit vs control 4  6 months 0.80means 25% increment of the benefit vs control 4  5 months Target delta: HR fantastic very good hmm…

14. median HR PFS.57 OS.73 Sobrero and Bruzzi, JCO 2009 15 pivotal R phase III registration trials, 9 biologics, 8 cancer types median absolute gain 2.7 months 2.0 months Very good / fantastic …hmm…

15. 1.HR vs absolute delta 2.target HR in trial design vs p value in trial analysis and interpretation. 3.low target HR in trial design The 3 problems

16. PROBLEM 1: ABSOLUTE GAIN Increase in median OS for different HR as a function of prognosis MST Increase in median values as a function of HR In control 0.90.80.70.60.50.4 6.61.52469 worthless worthwhile Unrealistic 24 2.6 6 10 16 24 36 Clinically worthwhile relative delta is a function of prognosis Both HR AND absolute gain must be considered

17. PROBLEM 2: INCONSISTENCY DESIGNCONDUCTANALYSIS REPORT INTERPRET. Define target delta…………....target delta is ignored and... p value becomes the focus…

18. Problem 3 : INCONSISTENCY HR 0.4 0.5 0.6 0.7 0.8 0.9 1.0 H1H1 H 0 NEG POSITIVE POS

19. ‘Statistically positive’ trials with deltas lower than those pre-specified in the protocol AUTHOR DRUGTUMOR predefined reportedp HR HR value Johnstone 09lapatinibbreast 0.64 0.71 0.019 Jonker 07cetuximabcolon 0.74 0.77 0.001 Moore 07erlotinibpancreas 0.75 0.82 0.038 Llovet 08sorafenibliver 0.6 0.69 0.001 Escudier 07sorafenibrenal 0.67 0.72 0.02 modified from Ocana A. JNCI,2011

20. PROBLEM 3. ‘ LOW PROFILE’ Typical phase III trial design in advanced cancer (PFS 6 mo) Delta 25% i.e. HR =.75 Median delta = 1.8 mo Power 90% N = 800 Cost = 100 M If we get this, is this really clinically worthwhile? Be more corageous : raise the bar

21. TML OS: ITT population OS estimate Time (months) 1.0 0.8 0.6 0.4 0.2 0 0612182430364248 No. at risk CT41029316251247320 BEV + CT409328188642913410 CT (n=410) BEV + CT (n=409) 9.8 mo11.2 mo Unstratified a HR: 0.81 (95% CI: 0.69–0.94) p=0.0062 (log-rank test) Stratified b HR: 0.83 (95% CI: 0.71–0.97) p=0.0211 (log-rank test) a Primary analysis method; b Stratified by first-line CT (oxaliplatin-based, irinotecan-based), first-line PFS (≤9 months, >9 months), time from last dose of BEV (≤42 days, >42 days), ECOG performance status at baseline (0, ≥1) Median follow-up: CT, 9.6 months (range 0–45.5); BEV + CT, 11.1 months (range 0.3–44.0)

22. VELOUR Overall Survival - ITT Population Cut-off date = February 7, 2011; Median follow-up = 22.28 months

23. CORRECT Overall survival Primary endpoint met prespecified stopping criteria at interim analysis (1-sided p<0.009279 at approximately 74% of events required for final analysis) 1.00 0.50 0.25 0 0.75 200100500150300250400350450 Days from randomization Survival distribution function Placebo N=255 Regorafenib N=505 Median 6.4 mos 5.0 mos 95% CI 5.9–7.3 4.4–5.8 Hazard ratio: 0.77 (95% CI: 0.64–0.94) 1-sided p-value: 0.0052 RegorafenibPlacebo

24. The different aspects of clinical benefit 1.HR 2.Median 3.% at prespecified time 4.% cure/ long term survivors 5.Clinically meaningful responses 6.Toxicity and logistical convenience

25. Conclusions 1.‘critical’ HR of around 0.75 is appropriate for most conditions 2.Primary endpoint depends on setting 3.All other parameters of efficacy and toxicity must be evaluated to correctly interpret the clinical relevance of ‘incrementalist’ delta.