# Presentation: 848395

## Progression as an endpoint in CRC

- Kevin Carroll, BSc, MSc, FRSS,
- Global Statistical Leader, Oncology, AstraZeneca Pharmaceuticals

## Progression is a meaningful endpoint in CRC trials

- AstraZeneca’s phase III trial program data provide evidence to support PFS as a surrogate for survival in 1st line CRC.
- Recent literature is supportive, with improvements in PFS generally followed by improvements in survival.
- An ‘event count’ analysis provides a simple alternative to the analysis of PFS time and avoids concerns with respect to the determination of the time of progression.
- Progression is a meaningful endpoint in 1st line CRC1,2, improvements in which represent a patient benefit and, as such, should be employed as the primary endpoint in clinical trials.

- 1Di Leo et al, Annals of Oncology 2004; 2DeGramont et al, JCO, 2000

## Tomudex vs. 5FU-LV in 1st line CRC

- 3, multicenter, international randomized phase III trials in 1361 patients.
- Trials of similar design, similar incl./excl. criteria and commonly defined endpoints.
- One trial (00101) conducted in North America, two trials (00032 and 00123) predominantly in Europe and Australia.

- 1Pazdur, Proc ASCO 1997; 2Cunningham, Annals of Oncology, 1996; 3Cocconi, JCO, 1998.

## PFS and survival outcomes in the Tomudex trials

|  | Progression-Free Survival |  | Overall Survival |  |
| --- | --- | --- | --- | --- |
| Trial | TomudexEvents (%) | 5FU-LVEvents (%) | TomudexEvents (%) | 5FU-LVEvents (%) |
| 0003 (N=439) | 223 (94.6) | 216 (94.4) | 165 (74.0) | 152 (70.4) |
| 0010 (N=427) | 205 (94.5) | 192 (91.4) | 163 (75.1) | 136 (64.8) |
| 0012 (N=495) | 205 (84.6) | 195 (78.6) | 123 (49.8) | 119 (48.0) |
| All (N=1361) | 625 (91.0) | 591 (87.7) | 451 (65.7) | 407 (60.4) |
|  | HR* & 95% CI 1.30 (1.16, 1.46) |  | HR* & 95% CI 1.17 (1.03, 1.34) |  |

- *HR=Hazard ratio from an unadjusted log rank test

## Evidence PFS is a surrogate for survival in the Tomudex program 

- 53% of the treatment effect on survival is explained by the effect of treatment on PFS1,2.
- Survival is not significant after adjustment for PFS;HR = 1.08 (0.94, 1.23), p=0.27.
- The relative effect3 of treatment on survival vs. PFS is estimated to be 0.60 (0.30, 0.90).
- If PFS increases by 50%, expect survival to increase by 27% 95% CI (13%, 44%).

- 1Prentice, Stat in Med, 1989; 2Freedman et al, Stat in Med, 1992; 2Buyse and Molenbergs, 1998.

## Positive association between treatment effects on survival and PFS in 1st line Tomudex CRC trials   

- Log HR for PFS

- Log HR for OS

- r=0.66, p=0.0012

-  = region
-  = Trial

- Size of circle proportionalto N pts in region/trial.

- Positive association between treatment effects on survival and PFS in 1st line Tomudex CRC trials

## Evidence PFS is a surrogate for survival in the Tomudex program 

- 53% of the treatment effect on survival is explained by the effect of treatment on PFS1,2.
- Survival is not significant after adjustment for PFS;HR = 1.08 (0.94, 1.23), p=0.27.
- The relative effect3 of treatment on survival vs. PFS is estimated to be 0.51 (0.11, 0.91).
- If PFS increases by 50%, expect survival to increase by 29% 95% CI (13%, 48%).

- 1Prentice, Stat in Med, 1989; 2Freedman et al, Stat in Med, 1992; 2Buyse and Molenbergs, 1998.

## Positive association between treatment effects on survival and PFS in 1st line Tomudex CRC trials   

- Log HR for PFS

- Log HR for OS

- r=0.48, p=0.0247

-  = region
-  = Trial

- Size of circle proportionalto N pts in region/trial.

- Positive association between treatment effects on survival and PFS in 1st line Tomudex CRC trials

## PFS and survival data from recently completed trials in 1st line CRC

| Comparison | Reference | Total No. of patients | Effect† on PFS | Effect† on survival |
| --- | --- | --- | --- | --- |
| IFL v FL | Saltz1 | 457 | +56%* | +28%* |
| IFL v FL | Douillard2 | 385 | +69%* | +23%*# |
| Oxali +FL v FL | DeGramont3 | 420 | +72%* | +25%* |
| Oxali +FL v FL | Giacchetti4 | 200 | +43%*# | -3%NS# |
| Bevac +IFL v IFL | Hurwitz5  | 815 | +85%* | +54%* |
| Oxali +FL vs. IFL  | Goldberg6 | 531 | +35%* | +52%* |
| Oxali +FL vs. IrOx | Goldberg6 | 528 | +39%* | +20%NS |

- 1NEJM, 2000; 2Lancet, 2000; 3JCO, 2000; 4JCO, 2000; 5Proc ASCO, 2003; 6JCO, 2004;

- *2p<0.05.  #ratio of medians. †Inverse hazard ratio.

## Survival Time

- Visit 1

- Visit 2

- Randomization

- = Date of Death or actual tumor progression

- Survival Event Date

- Visit 1

- Visit 2

- Randomization

- TTP Event Date

- PFS Time

- Actual PFS time is often unknown in clinical trials1,2

- 1 Slide adapted from Dr G Williams, web link; 2 Williams et al, Proc ASCO, 2002.

## Using overall ‘event count’ to comparetreatments for progression outcome1,2,3

- As an alternative to PFS time, treatments could be compared on the overall event count over the trial follow-up period
- free from concerns and potential biases associated with the timing of the event.
- can derive the relative risk (RR) of progression between treatments.
- Little loss in statistical power under most circumstances providing fewer than 75-80% of patients have progressed.
- Is more powerful if treatment effect is delayed.

- 1 Cuzick, Biometrics, 1982; 2 Gail, Cont Clinical Trials, 1985; 3 Carroll, Clinical Trials, submitted 2004.

##  Overall event count analysis provides similar results compared to conventional PFS time, log rank analyses

- Follow-up time (weeks)

- Treatment effect and 95% CI

-  = Hazard ratio = Relative risk

-  Overall event count analysis provides similar results compared to conventional PFS time, log rank analyses

- Tomudex vs. 5FU in 1st line CRC (Trial 0003)

## Summary

- AstraZeneca’s phase III trial program data provide evidence to support PFS as a surrogate for survival in 1st line CRC.
- Recent literature is supportive, with improvements in PFS generally followed by improvements in survival.
- An ‘event count’ analysis provides a simple alternative to the analysis of PFS time and avoids concerns with respect to the determination of the time of progression.
- Progression is a meaningful endpoint in 1st line CRC1,2, improvements in which represent a patient benefit and, as such, should be employed as the primary endpoint in clinical trials.

- 1Di Leo et al, Annals of Oncology 2004; 2DeGramont et al, JCO, 2000