NCIC CTG MA.17 Updated Analysis Post-Unblinding

1. NCIC CTG MA.17 Updated Analysis Post-Unblinding PE Goss on behalf of the MA.17 Collaborative Trialists Group

2. MA.17: Trial Design Randomization (all patients disease-free) 0-3months Letrozole 2.5 mg daily n=2593 Tamoxifen Placebo daily n=2594 ~ 5 years 5 years extended adjuvant Primary end point: DFS Secondary end points: OS / rate of contralateral breast cancer/ safety / QOL Goss PE et al: J Natl Cancer Inst 97:1262, 2005

3. MA.17: Pre-Planned AnalysisKey Endpoints in Nodal Subgroups (n=5187)Letrozole reduced risk of recurrence by 42% HR=0.45 (0.27-0.75) HR=0.63 (0.31-1.27) HR=1.52 (0.76-3.06) Node* neg Node neg Node neg HR=0.82 (0.57-1.19) Distant* DFS DFS* OS HR=0.58 (0.45-0.76) HR=0.61 Node* pos Node* pos Node* pos HR=0.61 (0.45-0.84) HR=0.53 (0.36-0.78) HR=0.61 (0.38-0.98) * Statistically significant Goss P et al, J Natl Cancer Inst 2005; 97:1262-71

4. Unblinding of MA.17 • First Interim Analysis: p = 0.00004 for DFS • Trial unblinded on advice of DSMC (independent data safety and monitoring committee) to offer women who had been on placebo (PLAC) for 1-5 years an opportunity to take letrozole (LET) for an additional 5 years • Regardless of early stopping, MA17 like other recent AI trials was not designed to address optimal duration

5. Goals of this Study • To determine whether women switching from PLAC to LET benefit in terms of disease outcome • To evaluate treatment related toxicities in women switching from PLAC to LET

6. Endpoints Evaluated • Disease-free survival (DFS) • Events: any breast cancer recurrence or a contralateral breast cancer • Distant disease-free survival (DDFS) • Event: distant metastasis • Overall survival (OS) • Event: death, any cause

7. MA.17 Post-Unblinding Cohorts Median F/U 30 Months 54 (16 –86) Months Letrozole n= 2593 Letrozole (LET) n = 2457 Tamoxifen n = 5187 No Letrozole (PLAC) n = 613 Placebo n= 2594 5 years 5 years Letrozole (PLAC-LET) n = 1655 1998 2003 2005 Unblinding Ingle et al Goss et al

8. Significantly Different Baseline Characteristics (All p<0.01)

9. Significantly Different Baseline Characteristics (All p<0.01)

10. Summary of Post-Unblinding Cohorts • Those switching (PLAC-LET) were younger, had more advanced disease, had a worse performance status and were more likely to have had adjuvant chemotherapy • Those remaining on no treatment (PLAC) were older with lower stage disease and reasons for remaining off treatment may have included better prognosis from breast cancer but higher co-morbid disease • Those continuing active treatment (LET) had fewer events pre-unblinding and are thus not comparable to either PLAC or PLAC-LET groups

11. Statistical Methods • All patients who recurred or died before the date of unblinding were removed from the analyses • Toxicity analysis includes only events after unblinding • Hazard ratios and p-values are calculated from Cox models adjusting for all factors found significant in the univariate analysis

12. Percentage of Patients with Recurrence

13. Percentage of Breast Cancer and Other Cause Mortality

14. 100 PLAC-LET PLAC 80 60 e Disease Free Survival g a t n Adjusted HR 0.31 (0.18, 0.55 : p <0.0001) e 40 c r e P 20 Time from randomization (months) 0 0.0 20.0 40.0 60.0 80.0 1655 1631 914 232 3 613 594 406 156 4 # At Risk(PLAC-LET) # At Risk(PLAC)

15. 100 80 PLAC-LET PLAC 60 e g a Distant Disease Free Survival t n e 40 c r Adjusted HR 0.28 (0.13, 0.62: p = 0.002) e P 20 Time from randomization (months) 0 0.0 20.0 40.0 60.0 80.0 1655 1631 914 232 3 613 594 406 156 4 # At Risk(PLAC-LET) # At Risk(PLAC)

16. 100 80 PLAC-LET PLAC 60 e g a Overall Survival t n e 40 c Adjusted HR 0.53 (0.28, 1.00: p = 0.05 ) r e P 20 Time from randomization (months) 0 0.0 20.0 40.0 60.0 80.0 1655 1632 919 236 3 613 595 416 161 4 # At Risk(PLAC-LET) # At Risk(PLAC)

17. 100 ) 0 0 0 , PLAC-LET PLAC 80 1 r e Contralateral Breast Cancer p ( 60 Adjusted HR 0.23 (0.07, 0.77; p = 0.017) e t a R 40 e v i t a l 20 u m m u C 0 0.0 20.0 40.0 60.0 80.0 1655 1600 681 59 0 613 580 317 60 0 # At Risk(PLAC-LET) Time from randomization (months) # At Risk(PLAC)

18. Adjusted HR (PLAC-LET to PLAC) for Efficacy Outcomes p=0.05 p<0.0001 p=0.002 p=0.012

19. MA.17 Post-Unblinding Toxicity Analyses Median F/U 30 Months 54 Months LET Letrozole n = 2457 Letrozole n= 2593 Tamoxifen n = 5187 PLAC Placebo n= 2594 n= 613 5 years 5 years PLAC - LET Letrozole n = 1655 1998 2003 2005 Unblinding

20. Adverse Events After Unblinding P=0.84 P=0.007 P=0.60

21. Conclusions MA.17 Post-Unblinding TOXICITY: • Post-Unblinding there was a numerical trend toward more clinical fractures between PLAC-LET and PLAC patients but it did not reach statistical significance • New diagnoses of osteoporosis was higher in PLAC-LET treated patients • No difference in cardiac events was detected between PLAC-LET and PLAC treated patients

22. Conclusions MA.17 Post-Unblinding EFFICACY: • It is recognized that the two groups compared post unblinding had different baseline characteristics but if anything the women electing to switch to LET had a higher risk of disease recurrence • To account for the imbalance between the two groups a multivariate analysis including the key variables was undertaken • Women with hormone dependent breast cancer prescribed LET after a prolonged delay from completing Tamoxifen experienced a significant improvement in outcome (DFS, DDFS and OS) and should be considered for this therapy

23. Conclusions MA.17 Post-Unblinding EFFICACY (cont’d): • The observed improvement in outcome in women on PLACEBO switching to LETROZOLE justifies the DSMC decision to unblind the MA.17 trial early and met the ethical obligations of the trialists to the women who consented to participate on MA.17