Which difference should we target?

Alberto Sobrero

Ospedale San Martino IRCCS

Genova, Italy

Which delta should we target?

• Delta for deciding GO - NO GO to phase III(signal generating trials)

• Delta of phase III

• Delta for deciding GO - NO GO to phase III(signal generating trials)

• Delta of phase III

Randomized Phase II

Bendell JCO 2011Bendell 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)

Overall Survival – All Patients

Progression Free Survival – All Patients

• 1 Does 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 ?

• 2 To what extent? How sure are we of the size of

the activity ?

• 3 Is 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

PFS on study vs PFS on prior regimenPFS on study vs PFS on prior regimen

PFS on study vs PFS on prior regimensPFS on study vs PFS on prior regimens

NONO

NONO

NONO

NONO

NONO

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.

• 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.

Size of benefit (target delta) :

a compromise

1. plausible to achieve

2. worthwhile if achieved

Target delta: HR

fantastic

very

good

hmm…

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 / f

antastic

…hmm…

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

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 HRIn control

0.9 0.8 0.7 0.6 0.5 0.4

6 .6 1.5 2 4 6 9

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

PROBLEM 2: INCONSISTENCY

DESIGN CONDUCT ANALYSIS REPORT INTERPRET.

Define target delta…………....target delta is ignored and... p value becomes the focus…

Problem 3 : INCONSISTENCY

HR 0.4 0.5 0.6 0.7 0.8 0.9 1.0

H1 H0

NEG

POSITIVE

POS

POS

‘Statistically positive’ trials with deltas lower than those pre-specified

in the protocol

AUTHOR DRUG TUMOR predefined reported p HR HR value

Johnstone 09 lapatinib breast 0.64 0.71 0.019Jonker 07 cetuximab colon 0.74 0.77 0.001Moore 07 erlotinib pancreas 0.75 0.82 0.038Llovet 08 sorafenib liver 0.6 0.69 0.001Escudier 07 sorafenib renal 0.67 0.72 0.02

modified from Ocana A. JNCI,2011

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 MIf w

e get this , is

this really clinically worthwhile?

Be more corageous : raise the bar

TML OS: ITT populationO

S e

stim

ate

Time (months)

1.0

0.8

0.6

0.4

0.2

00 6 12 18 24 30 36 42 48

No. at riskCT 410 293 162 51 24 7 3 2

0BEV + CT 409 328 188 64 29 13 4 1

0

CT (n=410)BEV + CT (n=409)

9.8 mo 11.2 mo

Unstratifieda HR: 0.81 (95% CI: 0.69–0.94)

p=0.0062 (log-rank test)

Stratifiedb HR: 0.83 (95% CI: 0.71–0.97)

p=0.0211 (log-rank test)

aPrimary analysis method; bStratified 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)

VELOUR Overall Survival - ITT Population

Cut-off date = February 7, 2011; Median follow-up = 22.28 months

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

200100500 150 300250 400350 450

Days from randomization

Sur

viva

l dis

trib

utio

n fu

nctio

n

Placebo N=255Regorafenib N=505

Median 6.4 mos 5.0 mos95% 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

Regorafenib Placebo

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

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.