NCIC CTG MA.17

Updated Analysis Post-Unblinding

NCIC CTG MA.17

Updated Analysis Post-Unblinding

PE Goss on behalf of the MA.17 Collaborative Trialists Group

PE Goss on behalf of the MA.17 Collaborative Trialists Group

MA.17: Trial Design

Primary end point: DFS

Secondary end points: OS / rate of contralateral breast cancer/ safety /

QOL

Randomization(all patients disease-free)

Tamoxifen

Placebo daily

Letrozole 2.5 mg daily

~ 5 years 5 years extended adjuvant

0-3months n=2593

n=2594

Goss PE et al: J Natl Cancer Inst 97:1262, 2005Goss PE et al: J Natl Cancer Inst 97:1262, 2005

MA.17: Pre-Planned AnalysisKey Endpoints in Nodal Subgroups

(n=5187) Letrozole reduced risk of recurrence by 42%

DFS* Distant* DFS

Node* pos

Node* pos

Node* neg

Node neg

Node neg

Node* pos

* Statistically significant

HR=0.61(0.45-0.84)

HR=0.45(0.27-0.75)

HR=0.63(0.31-1.27)

HR=0.53(0.36-0.78)

HR=1.52(0.76-3.06)

HR=0.61(0.38-0.98)

Goss P et al, J Natl Cancer Inst 2005; 97:1262-71

HR=0.58(0.45-0.76)

HR=0.61

HR=0.82(0.57-1.19)OS

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

• 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

Goals of this Study

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

MA.17 Post-Unblinding Cohorts

Tamoxifenn = 5187

Placebo n= 2594

5 years5 years

Letrozole (PLAC-LET) n = 1655

1998 2003 2005

Letrozole n= 2593

Unblinding

Ingle et al Goss et al

Letrozole (LET) n = 2457

No Letrozole (PLAC) n = 613

30 Months 54 (16 –86) Months

Median F/U

Significantly Different Baseline Characteristics (All p<0.01)

80

66

9296

0102030405060708090

100

Per

cen

t

Age < 70 ECOG = 0

PLAC-LET PLAC

Significantly Different Baseline Characteristics (All p<0.01)

4957

49

33

0102030405060708090

100

Per

cen

t

Node Neg Prior chemo

PLAC-LET PLAC

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

Statistical Methods

1. All patients who recurred or died before the date of unblinding were removed from the analyses

2. Toxicity analysis includes only events after unblinding

3. Hazard ratios and p-values are calculated from Cox models adjusting for all factors found significant in the univariate analysis

Percentage of Patients with Recurrence

1.5

0.2

1.3

0.4

2.4

0.5

1.4

0.24

0

0.5

1

1.5

2

2.5

Per

cen

t

New PrimaryOnly

Local-regional

Distant CBC

PLAC PLAC-LET

Percentage of Breast Cancer and Other Cause Mortality

0.8

0.4

1

0.5

0

0.5

1

1.5

2

2.5

Per

cen

t

Breast Cancer Other Causes

PLAC PLAC-LET

PLAC-LET PLAC

Pe

r cen

tage

0

20

40

60

80

100

Time from randomization (months)

# At Risk(PLAC-LET)

# At Risk(PLAC)

0.01655

613

20.01631

594

40.0914

406

60.0232

156

80.03

4

Disease Free Survival

Adjusted HR 0.31 (0.18, 0.55 : p <0.0001)

PLAC-LET PLAC

Pe

r cen

tage

0

20

40

60

80

100

Time from randomization (months)

# At Risk(PLAC-LET)

# At Risk(PLAC)

0.01655

613

20.01631

594

40.0914

406

60.0232

156

80.03

4

Distant Disease Free Survival

Adjusted HR 0.28 (0.13, 0.62: p = 0.002)

PLAC-LET PLAC

Pe

r cen

tage

0

20

40

60

80

100

Time from randomization (months)

# At Risk(PLAC-LET)

# At Risk(PLAC)

0.01655

613

20.01632

595

40.0919

416

60.0236

161

80.03

4

Overall Survival

Adjusted HR 0.53 (0.28, 1.00: p = 0.05 )

PLAC-LET PLAC

0

20

40

60

80

100

Time from randomization (months) # At Risk(PLAC-LET)

# At Risk(PLAC)

0.01655

613

20.01600

580

40.0681

317

60.059

60

80.00

0

Contralateral Breast Cancer

Cum

mu

lati

ve R

ate

(pe

r 1

, 000

)

Adjusted HR 0.23

(0.07, 0.77; p = 0.017)

Adjusted HR (PLAC-LET to PLAC) for Efficacy Outcomes

0.310.28

0.53

0.23

0

0.1

0.2

0.3

0.4

0.5

0.6

PLAC-LET to PLAC

Disease Free Survival Distant Disease Free Survival

Overall Survival Contralateral Breast Cancer

p<0.0001p=0.002

p=0.05

p=0.012

MA.17 Post-Unblinding Toxicity Analyses

Tamoxifenn = 5187

Placebo n= 2594

5 years5 years

n= 613

Letrozole n = 1655

1998 2003 2005

Letrozole n= 2593

Unblinding

LET

PLAC

PLAC - LET

Letrozole n = 2457

30 Months 54 Months

Median F/U

Adverse Events After Unblinding

0.0%

0.5%

1.0%

1.5%

2.0%

2.5%

3.0%

3.5%

4.0%

Bone Fracture New Osteoporosis CV Disease

PLAC-LET PLAC

P=0.60

P=0.007 P=0.84

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

Conclusions MA.17 Post-UnblindingEFFICACY:

• 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

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